Modified aminoacids, pharmaceuticals containing these compounds and method for their production

ABSTRACT

The present invention relates to modified amino acids of general formula                    
     wherein 
     A, Z, X, n, m, R, R 2 , R 3 , R 4  and R 11  are defined as in claims 1 to 5, their tautomers, their diastereomers, their enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for preparing them as well as their use for the production and purification of antibodies and as labelled compounds in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.

The present invention relates to modified amino acids of general formula

their tautomers, their diastereomers, their enantiomers, their mixturesand salts thereof, particularly physiologically acceptable salts thereofwith inorganic or organic acids or bases, pharmaceutical compositionscontaining these compounds, the use thereof and processes for preparingthem.

In the above general formula I

R denotes an unbranched C₁₋₇-alkyl group which may be substituted in theω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylylgroup,

by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-2H-2-oxoimidazopyridinyl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-ylgroup, wherein the latter two groups may each be mono- or disubstitutedin the 4- and/or 5-position or in the 5- and/or 6-position by lowerstraight chained or branched alkyl groups, by phenyl, biphenylyl,pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or1-methylimidazolyl groups and the substituents may be identical ordifferent,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or additional nitrogen atom,whilst a nitrogen atom of an imino group may be substituted by an alkylgroup,

or by a 6-membered heteroaromatic ring linked via a carbon atom, whichcontains one, two or three nitrogen atoms,

whilst a 1,4-butadienylene group may be attached both to theabove-mentioned 5-membered heteroaromatic monocyclic rings and to the6-membered heteroaromatic monocyclic rings, in each case via twoadjacent carbon atoms, and the bicyclic heteroaromatic rings thus formedmay also be bound via a carbon atom of the 1,4-butadienylene group,

an unbranched C₁₋₆-alkylamino group optionally substituted at thenitrogen atom by a C₁₋₆-alkyl group or by a phenylmethyl group, whichmay be substituted in the ω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylylgroup,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or an additional nitrogenatom, whilst a nitrogen atom of an imino group may be substituted by analkyl group, or

by a 6-membered heteroaromatic ring linked via a carbon atom, containing1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may beattached both to the 5-membered and to the 6-membered heteroaromaticmonocyclic rings, in each case via two adjacent carbon atoms, and thebicyclic heteroaromatic rings thus formed may also be bound via a carbonatom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkyl and alkylamino groups in the ω-positionand optionally also partially hydrogenated mono- and bicyclicheteroaromatic rings in the carbon skeleton may additionally be mono-,di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkylgroups, C₃₋₈-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, wherein the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino andbenzoylmethylamino groups may in turn additionally be substituted in thephenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl,trifluoromethyl, amino or acetylamino group, or the group of formula

 wherein

p denotes the number 1 or 2,

o denotes the number 2 or 3 or, if Y¹ and Y² are not simultaneouslynitrogen atoms, o may also denote 1.

Y¹ denotes the nitrogen atom if R⁵ is a free pair of electrons, or thecarbon atom,

Y² is the nitrogen atom or the group >CH—,

R⁵ is a free pair of electrons if Y¹ denotes the nitrogen atom or, if Y¹denotes the carbon atom, R⁵ denotes a hydrogen atom, a C₁₋₃-alkyl group,a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl,aminocarbonylamino, phenylmethyl or phenyl group,

R⁶ denotes the hydrogen atom or, provided that Y¹ is not a nitrogenatom, R⁶ together with R⁵ may denote an additional bond,

R⁷ denotes the hydrogen atom or, provided that Y¹ is not a nitrogen atomand R⁵ and R⁶ together constitute an additional bond, R⁷ together withR^(N) may also denote a 1,4-butadienylene group,

R^(N) denotes a hydrogen atom or a C₁₋₆-alkyl group which may be mono-or disubstituted in the ω-position

by a C₅₋₇-cycloalkyl group, by a 1-naphthyl, 2-naphthyl, hydroxy,alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl,pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl,alkylaminocarbonyl, acetylamino, cyano, aminocarbonylamino oralkylaminocarbonylamino group or by phenyl, pyridinyl or diazinylgroups, whilst these substituents may be identical or different,

a C₅₋₇-cycloalkyl group, a phenyl, pyridinyl, cyano, amino,benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl,phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino,N-(alkylaminocarbonyl)-N-alkylamino,N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino,[phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino,N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino,phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino,N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino,N-(aminocarbonylaminocarbonyl)-N-phenylamino,N-(pyridinyl)-N-(aminocarbonyl)amino,N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino,4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl or diazinylaminogroup,

a saturated, mono- or di-unsaturated 5- to 7-membered aza, diaza,triaza, oxaza, thiaza, thiadiaza- or S,S-dioxido-thiadiaza-heterocycle.

wherein the above-mentioned heterocycles may be linked via a carbon ornitrogen atom and

may contain one or two carbonyl groups adjacent to a nitrogen atom,

may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl,aroyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl,phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,

may be substituted at one or two carbon atoms by a branched orunbranched alkyl group or by a phenyl, phenylmethyl, naphthyl,biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or1-methylimidazolyl group, wherein the substituents may be the same ordifferent,

and wherein a C₃₋₆-alkylene group may additionally be attached to theabove-mentioned heterocycles via two adjacent carbon atoms or anolefinic double bond of one of the above-mentioned unsaturatedheterocycles may be fused with a benzene, pyridine, diazine,1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole,quinoline, imidazole or N-methylimidazole ring,

or if Y¹ is not a nitrogen atom and R⁵ and R⁶ together denote anadditional bond, R^(N) together with R⁷ may also denote the1,4-butadienylene group,

or, if Y¹ is a carbon atom, R^(N) together with R⁵, including Y¹, alsodenotes a carbonyl group or a saturated or mono-unsaturated 5- or6-membered 1,3-diaza-heterocycle which may optionally contain one or twocarbonyl groups in the ring and, if it is unsaturated, may be benzofusedat the double bond and may be substituted at one of the nitrogen atomsby a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl,phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,

whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl,1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl,imidazolyl- or 1-methylimidazolyl groups contained in the residuesmentioned under R⁵, R⁷ and R^(N), as well as benzo, thieno, pyrido- anddiazino-fused heterocycles in the carbon skeleton may additionally bemono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, byalkyl groups, C₃₋₈-cycloalkyl groups, nitro, alkoxy, alkylthio,alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl,phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl,carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl,alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy,trifluormethylthio, trifluoromethylsulphinyl- ortrifluoromethylsulphonyl groups, wherein the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino,benzoylaminocarbonylamino and benzoylmethylamino groups may in turnadditionally be substituted in the phenyl moiety by a fluorine, chlorineor bromine atom or by an alkyl, trifluoromethyl, amino- or acetylaminogroup

and unless otherwise specified the alkyl groups contained in theabove-mentioned radicals may contain 1 to 5 carbon atoms,

X denotes an oxygen atom or 2 hydrogen atoms,

Z denotes a methylene group or the group —NR¹, wherein

R¹ denotes a hydrogen atom or an alkyl or phenylalkyl group,

R¹¹ denotes a hydrogen atom, a C₁₋₃-alkyl group, an alkoxycarbonyl grouphaving a total of 2 to 4 carbon atoms or a phenylmethyl group,

n denotes the number 1 or 2 or, if m is 1, n may also be 0,

m denotes the number 0 or 1,

R² denotes a phenyl, 1-naphthyl, 2-naphthyl,1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl,1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl,4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl,1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl,benzo[b]thien-3-yl, pyridinyl, qui-nolinyl or isoquinolinyl group,

whilst the above-mentioned aromatic and heteroaromatic groups in thecarbon skeleton may additionally be mono-, di- or trisubstituted byfluorine, chlorine or bromine atoms or by branched or unbranched alkylgroups, C₃₋₈-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy,phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl,carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl,dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino,benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl,cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl,trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- ortrifluoromethylsulphonyl groups, and the substituents may be identicalor different and the above-mentioned benzoyl, benzoylamino- andbenzoylmethylamino groups may in turn additionally be substituted in thephenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl,trifluoromethyl, amino or acetylamino group,

A denotes a bond or the divalent group of formula

(which is linked to the NR³R⁴ group via the —CX group)

 wherein

R⁸ and R⁹ together denote an n-propylene group or

R⁸ denotes a hydrogen atom or an alkyl- or phenylalkyl group and

R⁹ denotes a hydrogen atom or a branched or unbranched C₁₋₅-alkyl groupwhich, if it is unbranched, may be substituted in the ω-position by ahydroxy, mercapto, amino, alkylamino, dialkylamino, 1-azetidinyl,1-pyrrolidinyl, 1-piperidinyl, hexahydro-1-azepinyl, methylthio,hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino,aminocarbonylamino, phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl,1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-naphthyl,2-naphthyl- or pyridinyl group, whilst the above-mentioned heterocycles,phenyl and naphthyl groups may in turn be mono-, di- or trisubstitutedin the carbon skeleton by fluorine, chlorine or bromine atoms or bymethyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino,aminocarbonyl, cyano, trifluoromethoxy, methylsulphonyloxy,trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, wherein the substituents may beidentical or different, and wherein the hydroxy, mercapto, amino,guanidino, indolyl and imidazolyl groups contained in the groupsmentioned for R⁹ may be substituted with the protecting groups commonlyused in peptide chemistry, preferably with the acetyl, benzyloxycarbonylor tert.butyloxycarbonyl group,

R³ denotes a hydrogen atom,

a C₁₋₇-alkyl group which may be substituted in the ω-position by acyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino,dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino,1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl,4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino,4-alkyl-1-piperazinyl or 4-(ω-hydroxyalkyl)-1-piperazinyl group,

a phenyl or pyridinyl group,

wherein the above-mentioned heterocyclic groups and phenyl groups mayadditionally be mono-, di- or trisubstituted in the carbon skeleton byfluorine, chlorine or bromine atoms or by methyl, alkoxy,trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano,methylsulphonyloxy, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and thesubstituents may be identical or different,

R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group optionally substitutedby a phenyl or pyridinyl group or

R³ and R⁴ together with the enclosed nitrogen atom denote a group ofgeneral formula

 wherein

Y³ denotes a carbon atom or, if R¹² denotes a free pair of electrons, Y³may also be the nitrogen atom,

r denotes the number 0, 1 or 2,

q denotes the number 0, 1 or 2,

R¹⁰ denotes a hydrogen atom or an amino, alkylamino, dialkylamino,alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino,cycloalkylaminocarbonylamino, phenylaminocarbonylamino,aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl or carboxy group,

a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl,pyridinylcarbonyl- or phenylcarbonyl-group which may be mono-, di- ortrisubstituted in the carbon skeleton by fluorine, chlorine or bromineatoms, or by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl,hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino,aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl,carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl,ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl,ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst thesubstituents may be identical or different,

a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, whichmay be substituted by a phenyl group or fused at the double bond to abenzene, pyridine or diazine ring,

a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl group,

a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza,thiaza- or diazacycloalkyl group or a 6- to 10-membered azabicycloalkylgroup,

wherein the above-mentioned mono- and bicyclic heterocycles may be boundvia a nitrogen or carbon atom and

may be substituted by a C₁₋₇-alkyl group, by an alkanoyl, dialkylamino,phenylcarbonyl, pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl,alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,alkylsulphonyl, cycloalkyl- or cycloalkylalkyl group, by acycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl oroxazacycloalkylcarbonyl group optionally substituted in the ring,

whilst the alicyclic parts contained in these substituents may comprise3 to 10 ring members and the heteroalicyclic parts may comprise 4 to 10ring members and

the above-mentioned phenyl and pyridinyl groups may in turn be mono- ,di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl,alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino,acetylamino, aminocarbonyl, aminocarbonylamino,aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl,carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl,ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst thesubstituents may be identical or different, or

R¹⁰ together with R¹² and Y³ denotes a 4- to 7-membered cycloaliphaticring in which a methylene group may be replaced by an —NH— or —N(alkyl)—group,

whilst a hydrogen atom bound to a nitrogen atom within the group R¹⁰ maybe replaced by a protecting group,

R¹² denotes a hydrogen atom,

a C₁₋₄-alkyl group, wherein an unbranched alkyl group may be substitutedin the co-position by a phenyl, pyridinyl, diazinyl, amino, alkylamino,dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl,4-morpholinyl- or hexahydro-1H-1-azepinyl group,

an alkoxycarbonyl, cyano or aminocarbonyl group or a free pair ofelectrons, if Y³ denotes a nitrogen atom, and

R¹³ and R¹⁴ in each case denote a hydrogen atom or,

if Y³ is a carbon atom, R¹² together with R¹⁴ also denotes anothercarbon-carbon bond, wherein R¹⁰ is as hereinbefore defined and R¹³denotes a hydrogen atom or

if Y³ is a carbon atom, R¹² together with R¹⁴ also denotes anothercarbon-carbon bond and R¹⁰ together with R¹³ and the enclosed doublebond denotes a partially hydrogenated or aromatic 5- to 7-membered mono-or bicyclic carbocycle or heterocycle,

whilst all the above-mentioned alkyl and alkoxy groups and the alkylgroups present within the other groups mentioned may contain 1 to 7carbon atoms, unless otherwise specified,

all the above-mentioned cycloalkyl groups and the cycloalkyl groupspresent within the other groups named may contain 5 to 10 carbon atoms,unless otherwise specified, and

the term “aroyl group” used above denotes, for example, the benzoyl ornaphthoyl group.

The protecting groups mentioned in the foregoing definitions andhereinafter are the protecting groups which are commonly known frompeptide chemistry, particularly

a phenylalkoxycarbonyl group having 1 to 3 carbon atoms in the alkoxymoiety, optionally substituted in the phenyl nucleus by a halogen atom,by a nitro or phenyl group or by one or two methoxy groups,

for example the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl,4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl,2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl,4-chloro-benzyloxycarbonyl, 4-Biphenylyl-α,α-dimethyl-benzyloxycarbonylor 3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group,

an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in thealkyl moiety,

for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl,2-methylpropoxycarbonyl or tert.butyloxycarbonyl group,

the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or9-fluorenylmethoxycarbonyl group or

the formyl, acetyl or trifluoroacetyl group.

The present invention relates to racemates, where the compounds ofgeneral formula I have only one chiral element. However, the applicationalso covers the individual diastereomeric pairs of antipodes or mixturesthereof which occur when there is more than one chiral element in thecompounds of general formula (I).

Particularly preferred are compounds of general formula I wherein Zdenotes NR¹ and m assumes the value 0 and which are in the D- or(R)-configuration with regard to the partial amino acid structure of theformula

and which are in the L- or (S)-configuration with regard to the partialamino acid structure of formula

which may be present in the group A. As for the other compounds coveredby general formula I, the preferred isomers are those which arespatially constructed analogously to the (R)-configured partialstructure of formula V with regard to the partial structure of formulaVI

The compounds of general formula I have valuable pharmacologicalproperties based on their selective CGRP-antagonistic properties. Theinvention further relates to medicaments containing these compounds,their use and the preparation thereof.

A subgroup of compounds of general formula I which deserves specialmention comprises those wherein

A, R², R³, R⁴, R¹¹, X, Z and m and n are as hereinbefore defined and

R denotes an unbranched C₁₋₆-alkylamino group optionally substituted atthe nitrogen atom by a C₁₋₆-alkyl group or by a phenylmethyl group,which may be substituted in the ω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylylgroup,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or an additional nitrogenatom, whilst a nitrogen atom of an imino group may be substituted by analkyl group, or

by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene groupmay be attached both to the 5-membered and to the 6-memberedheteroaromatic monocyclic rings via two adjacent carbon atoms in eachcase and the bicyclic heteroaromatic rings thus formed may also be boundvia a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkylamino groups in the ω-position andoptionally partially hydrogenated mono- and bicyclic heteroaromaticrings in the carbon skeleton may additionally be mono-, di- ortrisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups,C₃₋₈-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl- ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino-and benzoylmethylamino groups in turn may additionally be substituted inthe phenyl moiety by a fluorine, chlorine or bromine atom or by analkyl, trifluoromethyl, amino or acetylamino group,

whilst all the above-mentioned alkyl and alkoxy groups and the alkylgroups present within the other groups mentioned may contain 1 to 4carbon atoms, unless otherwise stated,

their tautomers, their diastereomers, their enantiomers, mixturesthereof and the salts thereof.

Another subgroup of compounds of general formula I deserving specialmention comprises those wherein

R², R³, R⁴, R¹¹, X, Z and m and n are defined as for the first subgrouphereinbefore,

R denotes an unbranched C₁₋₇-alkyl group which may be substituted in theω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- orbiphenylyl-group,

by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-2H-2-oxoimidazopyridinyl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,1,3-dihydro-2H-2-oxoimidazol-1-yl- or3,4-dihydro-2(1H)-oxopyrimidin-3-yl-groups, whilst the latter two groupsmay each be mono- or disubstituted in the 4- and/or 5-position or in the5- and/or 6-position by lower straight-chained or branched alkyl groups,by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl,1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl,imidazolyl or 1-methylimidazolyl groups, and the substituents may beidentical or different,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or in addition to a nitrogenatom contains an oxygen, sulphur or an additional nitrogen atom, whilsta nitrogen atom of an imino group may be substituted by an alkyl group,

or by a 6-membered heteroaromatic ring linked via a carbon atom, whichcontains one, two or three nitrogen atoms,

whilst a 1,4-butadienylene group may be attached both to theabove-mentioned 5-membered and to the 6-membered heteroaromaticmonocyclic rings, in each case via two adjacent carbon atoms, and thebicyclic heteroaromatic rings thus formed may also be bound via a carbonatom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl- and biphenylyl-groups mentionedhereinbefore for the substitution of the alkyl groups in the ω-positionand optionally partially hydrogenated mono- and bicyclic heteroaromaticrings in the carbon skeleton may additionally be mono-, di- ortrisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups,C₃ ₈-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino andbenzoylmethylamino groups may in turn additionally be substituted in thephenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl,trifluoromethyl, amino or acetylamino group, and

A denotes a single bond,

whilst all the above-mentioned alkyl and alkoxy groups and the alkylgroups present within the other groups mentioned may contain 1 to 4carbon atoms unless otherwise stated,

their tautomers, their diastereomers, their enantiomers and the saltsthereof.

Preferred compounds of the above general formula I are those wherein

R denotes an unbranched C₁₋₅-alkyl group which may be substituted in theω-position

by a C₄₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group,

by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-2H-2-oxoimidazopyridinyl,1,3-dihydro-2(2H)-oxoimidazo[4,5c]quinolin-3-yl,1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-ylgroup, whilst the latter two groups may each be mono- or disubstitutedin the 4- and/or 5-position or in the 5- and/or 6-positions by lowerstraight-chained or branched alkyl groups, by phenyl, biphenylyl,pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or1-methylimidazolyl groups, and the substituents may be identical ordifferent,

by a 5-membered heteroaromatic ring linked via a carbon atom andcontaining a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst anitrogen atom of an imino group may be substituted by an alkyl group,

or by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining one or two nitrogen atoms,

whilst a 1,4-butadienylene group may be attached both to the 5-memberedand to the 6-membered heteroaromatic monocyclic rings via two adjacentcarbon atoms in each case and the bicyclic heteroaromatic rings thusformed may also be bound via a carbon atom of the 1,4-butadienylenegroup,

or an unbranched C₁₋₄-alkylamino group optionally substituted at thenitrogen atom by a C₁₋₃-alkyl group or by a phenylmethyl group, whichmay be substituted in the ω-position

by a C₄₋₇-cycloalkyl group, by one or two phenyl groups, by a1-naphthyl, 2-naphthyl or (4-biphenylyl) group,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or1,3-dihydro-2H-2-oxo-imidazo[4,5-b]pyridin-3-yl group,

by a 5-membered heteroaromatic ring linked via a carbon atom andcontaining a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst anitrogen atom of an imino group may be substituted by an alkyl group,

or by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining 1 or 2 nitrogen atoms, whilst a 1,4-butadienylene group maybe attached to both the 5-membered and to the 6-membered heteroaromaticmonocyclic rings via two adjacent carbon atoms in each case and thebicyclic heteroaromatic rings thus formed may also be bound via a carbonatom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkyl and alkylamino groups in the ω-positionand optionally also partially hydrogenated mono- and bicyclicheteroaromatic rings in the carbon skeleton may additionally be mono-,di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkylgroups, C₅₋₇-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, wherein the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino andbenzoylmethylamino groups may in turn additionally be substituted in thephenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl,trifluoromethyl, amino or acetylamino group, or the group of formula

 wherein

p denotes the number 1 or 2,

o denotes the number 2 or, if Y¹ and Y² are not simultaneously nitrogenatoms, o may also denote 1.

Y¹ denotes the nitrogen atom if R⁵ is a free pair of electrons, or thecarbon atom,

Y² is the nitrogen atom or the group >CH—,

R⁵ is a free pair of electrons if Y¹ denotes the nitrogen atom or, if Y¹denotes the carbon atom, R⁵ denotes a hydrogen atom, a C₁₋₃-alkyl group,a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl,aminocarbonylamino, phenylmethyl or phenyl group,

R⁶ denotes the hydrogen atom or, provided that Y¹ is not a nitrogenatom, R⁶ together with R⁵ may denote an additional bond,

R⁷ denotes the hydrogen atom or, provided that Y¹ is not a nitrogen atomand R⁵ and R⁶ together constitute an additional bond, R⁷ together withR^(N) may also denote a 1,4-butadienylene group,

R^(N) denotes the hydrogen atom or a C₁₋₃-alkyl group, which may bemonosubstituted in the ω-position

by a C₅₋₇-cycloalkyl group or by a 1-naphthyl, 2-naphthyl, hydroxy,alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl,pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl,alkylaminocarbonyl, acetylamino, cyano, aminocarbonylamino oralkylaminocarbonylamino group, or may be mono- or disubstituted byphenyl, pyridinyl or diazinyl groups, whilst these substituents may beidentical or different,

a cyclohexyl, phenyl, pyridinyl, cyano, amino, benzoylamino,aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl,aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino,N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino,N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino,[N-phenyl(alkylamino)]carbonylamino,N-(phenylaminocarbonyl)-N-alkylamino,N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino,phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino,N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino,N-(aminocarbonylaminocarbonyl)-N-phenylamino,N-(pyridinyl)-N-(aminocarbonyl)amino,N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino,diazinylamino or 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinylgroup,

a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza,oxaza, thiaza, thiadiaza- or S,S-dioxidothiadiaza heterocycle,

whilst the above-mentioned heterocycles may be linked via a carbon ornitrogen atom and

may contain one or two carbonyl groups adjacent to a nitrogen atom,

may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl,aroyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl,phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,

may be substituted at one or two carbon atoms by a branched orunbranched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl,pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or1-methylimidazolyl group, whilst the substituents may be identical ordifferent,

and wherein a C₃₋₄-alkylene group may additionally be attached to theabove-mentioned heterocycles via two adjacent carbon atoms or anolefinic double bond of one of the above-mentioned unsaturatedheterocycles may be fused with a benzene, pyridine, diazine,1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole,quinoline, imidazole or N-methylimidazole ring,

or, provided that Y¹ is not a nitrogen atom and R⁵ and R⁶ togetherdenote an additional bond, R^(N) together with R⁷ may also denote the1,4-butadienylene group or,

if Y¹ denotes a carbon atom, R^(N) together with R⁵ , with the inclusionof Y¹, may also denote a carbonyl group or a saturated ormonounsaturated 5- or 6-membered 1,3-diazaheterocycle which may containone or two carbonyl groups in the ring adjacent to a nitrogen atom and,if it is unsaturated, may also be benzo-fused at the double bond andsubstituted at one of the nitrogen atoms by a methyl, aminocarbonyl,hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl,phenylmethyl or phenyl group,

whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl,1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl,imidazolyl or 1-methylimidazolyl groups contained in the residuesmentioned under R⁵, R⁷ and R^(N), as well as benzo-, thieno-, pyrido-and diazinofused heterocycles in the carbon skeleton may additionally bemono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, byalkyl groups, C₄₋₇-cycloalkyl groups, nitro, alkoxy, alkylthio,alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl,phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl,carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl,alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy,trifluormethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonylgroups, wherein the substituents may be identical or different and thealkyl groups contained in the above-mentioned groups may contain 1 to 3carbon atoms unless otherwise specified,

X denotes the oxygen atom or 2 hydrogen atoms,

Z denotes the methylene group or the group —NR⁵— wherein

R¹ denotes a hydrogen atom or a C₁₋₃-alkyl group,

R¹¹ denotes a hydrogen atom, a C₁₋₃-alkyl group or an alkoxycarbonylgroup having 2 to 4 carbon atoms altogether,

n denotes the number 1 or 2 or, if m is 1, n may also be 0,

m denotes the number 0 or 1,

R² denotes a phenyl, 1-naphthyl, 2-naphthyl,1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl,1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl,4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl,1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl,benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,

whilst the above-mentioned aromatic and heteroaromatic groups in thecarbon skeleton may additionally be mono-, di- or trisubstituted byfluorine, chlorine or bromine atoms, or by branched or unbranched alkylgroups, C₄₋₇-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy,phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl,carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl,dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino,benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl,cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl,trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, and the substituents may be identicalor different,

A denotes a bond or the divalent group of formula

(linked to the R³R⁴N— group of general formula (I) via the carbonylgroup)

 wherein

R⁸ and R⁹ together denote an n-propylene group or

R⁸ denotes a hydrogen atom or a C₁₋₃-alkyl group and

R⁹ denotes a hydrogen atom or a branched or unbranched C₁₋₄-alkyl groupwhich, if it is unbranched, may be substituted in the ω-position

by a hydroxy, mercapto, amino, alkylamino, dialkylamino, 1-azetidinyl,1-pyrrolidinyl, 1-piperidinyl, hexahydro-1-azepinyl, methylthio,hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino,aminocarbonylamino, phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl,1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-naphthyl,2-naphthyl- or pyridinyl group, whilst the above-mentioned heterocyclesand phenyl groups may in turn be mono-, di- or trisubstituted in thecarbon skeleton by fluorine, chlorine or bromine atoms, or by methyl,alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl,cyano, trifluoromethoxy, methylsulphonyloxy, trifluoromethylthio,trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst thesubstituents may be identical or different and any hydroxy, mercapto,amino, guanidino, indolyl and imidazolyl groups contained in the groupsmentioned for R⁹ may be substituted by a protecting group,

R³ denotes a hydrogen atom,

a C₁₋₄-alkyl group which may be substituted in the ω-position by acyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino,dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino,1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl,4-morpholinyl, hexahydro-1H-azepin-1-yl, [bis-(2-hydroxyethyl)]amino,4-methyl-1-piperazinyl- or 4-(ω-hydroxyalkyl)-1-piperazinyl group,

a phenyl or pyridinyl group,

wherein the above-mentioned heterocyclic radicals and phenyl groups mayadditionally be mono-, di- or tri-substituted in the carbon skeleton byfluorine, chlorine or bromine atoms or by methyl, alkoxy,trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano,methylsulphonyloxy, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and thesubstituents may be identical or different,

R⁴ denotes a hydrogen atom or a methyl or ethyl group optionallysubstituted by a phenyl or pyridinyl group

or R³ and R⁴ together with the enclosed nitrogen atom denote a group ofgeneral formula

 wherein

Y³ denotes a carbon atom or, if R¹² denotes a free pair of electrons, Y³may also be the nitrogen atom,

r denotes the number 0, 1 or 2,

q denotes the number 0, 1 or 2,

R¹⁰ denotes a hydrogen atom or an amino, alkylamino, dialkylamino,alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino,cycloalkylaminocarbonylamino, phenylaminocarbonylamino,aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl or carboxy group,

a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonylor phenylcarbonyl group which may be mono-, di- or trisubstituted in thecarbon skeleton by fluorine, chlorine or bromine atoms, or by alkyl,alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino,acetylamino, aminocarbonyl, aminocarbonylamino,aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl,carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl,ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl,ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphinyl-oder trifluoromethylsulphonyl groups, whilstthe substituents may be identical or different,

a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, whichmay be substituted by a phenyl group or fused at the double bond to abenzene, pyridine or diazine ring,

a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl group,

a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza,thiaza or diazacycloalkyl group or a 6- to 10-membered azabicycloalkylgroup,

wherein the above-mentioned mono- and bicyclic heterocycles may be boundvia a nitrogen or carbon atom and

may be substituted by a C₁₋₇-alkyl group, by an alkanoyl, dialkylamino,phenylcarbonyl, pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl,alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,alkylsulphonyl, cycloalkyl or cycloalkylalkyl group, by acycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl oroxazacycloalkylcarbonyl group optionally alkyl substituted in the ring,

whilst the alicyclic parts contained in these substituents may comprise3 to 10 ring members and the heteroalicyclic parts may comprise 4 to 10ring members and

the above-mentioned phenyl and pyridinyl groups may in turn be mono-,di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl,alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino,acetylamino, aminocarbonyl, aminocarbonylamino,aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl,carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl,ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst thesubstituents may be identical or different, or

R¹⁰ together with R¹² and Y³ denotes a 4- to 7-membered cycloaliphaticring in which a methylene group may be replaced by an —NH— or—N(alkyl)-group,

whilst a hydrogen atom bound to a nitrogen atom within the group R¹⁰ maybe replaced by a protecting group,

R¹² denotes a hydrogen atom, a C₁₋₂-alkyl group which may be substitutedin the ω-position by a phenyl, pyridinyl, diazinyl, amino, alkylamino,dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl,4-morpholinyl or hexahydro-1H-azepin-1-yl-group,

an alkoxycarbonyl, cyano- or aminocarbonyl group or a free pair ofelectrons, if Y³ denotes a nitrogen atom, and

R¹³ and R¹⁴ in each case denote a hydrogen atom or,

if Y³ is a carbon atom, R¹² together with R¹⁴ also denotes anothercarbon-carbon bond, wherein R¹⁰ is as hereinbefore defined and R¹³denotes a hydrogen atom or

if Y¹ is a carbon atom, R¹² together with R¹⁴ also denotes anothercarbon-carbon bond and R¹⁰ together with R¹³ and the enclosed doublebond denotes a partially hydrogenated or aromatic 5- to 7-membered mono-or bicyclic carbocycle or heterocycle,

whilst all the above-mentioned alkyl and alkoxy groups and the alkylgroups present within the other groups mentioned may contain 1 to 4carbon atoms, unless otherwise specified,

all the above-mentioned cycloalkyl groups and the cycloalkyl groupspresent within the other groups named may contain 5 to 7 carbon atoms,unless otherwise specified, and

the term “aroyl group” used above denotes, for example, the benzoyl ornaphthoyl group,

their tautomers, their diastereomers, their enantiomers and their salts.

One subgroup of preferred compounds of general formula I deservingspecial mention comprises those wherein

A, R², R³, R⁴, R¹¹, X, Z and m and n are defined as given hereinbeforedefined for the preferred compounds of general formula I,

R denotes an unbranched C₁₋₄-alkylamino group optionally substituted atthe nitrogen atom by a C₁₋₃-alkyl group or by a phenylmethyl group,which may be substituted in the ω-position

by a C₄₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or1,3-dihydro-2H-2-oxo-imidazo[4,5-b]pyridin-3-yl group,

by a 5-membered heteroaromatic ring linked via a carbon atom, andcontaining a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst anitrogen atom of an imino group may be substituted by an alkyl group,

or by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining 1 or 2 nitrogen atoms, whilst a 1,4-butadienylene group maybe attached both to the 5-membered and to the 6-membered heteroaromaticmonocyclic rings via two adjacent carbon atoms in each case and thebicyclic heteroaromatic rings thus formed may also be bound via a carbonatom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkylamino groups in the ω-position andoptionally partially hydrogenated mono- and bicyclic heteroaromaticrings in the carbon skeleton may additionally be mono-, di- ortrisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups,C₅₋₇-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino-and benzoylmethylamino groups in turn may additionally be substituted inthe phenyl moiety by a fluorine, chlorine or bromine atom or by analkyl, trifluoromethyl, amino or acetylamino group,

whilst all the above-mentioned alkyl and alkoxy groups and the alkylgroups present within the other groups mentioned may contain 1 to 4carbon atoms, unless otherwise stated,

their tautomers, their diastereomers, their enantiomers, mixturesthereof and the salts thereof.

Another subgroup of compounds of general formula I deserving specialmention comprises those wherein

R², R³, R⁴, R¹¹, X, Z and m and n are defined as for the first preferredsubgroup hereinbefore,

R denotes an unbranched C₁₋₅-alkyl group which may be substituted in theω-position

by a C₄₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group,

by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-2H-2-oxoimidazopyridinyl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-ylgroup, whilst the latter two groups may each be mono- or disubstitutedin the 4- and/or 5-position or in the 5- and/or 6-position by lowerstraight-chained or branched alkyl groups, by phenyl, biphenylyl,pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or1-methylimidazolyl groups, and the substituents may be identical ordifferent,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or in addition to a nitrogenatom contains an oxygen, sulphur or an additional nitrogen atom, whilsta nitrogen atom of an imino group may be substituted by an alkyl group,

or by a 6-membered heteroaromatic ring linked via a carbon atom, whichcontains one or two nitrogen atoms,

whilst a 1,4-butadienylene group may be attached both to the 5-memberedand to the 6-membered heteroaromatic monocyclic rings, in each case viatwo adjacent carbon atoms, and the bicyclic heteroaromatic rings thusformed may also be bound via a carbon atom of the 1,4-butadienylenegroup,

whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbeforefor the substitution of the alkyl groups in the ω-position andoptionally partially hydrogenated mono- and bicyclic heteroaromaticrings in the carbon skeleton may additionally be mono-, di- ortrisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups,C₅₋₇-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino andbenzoylmethylamino groups may in turn additionally be substituted in thephenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl,trifluoromethyl, amino or acetylamino group, and

A denotes a single bond,

whilst all the above-mentioned alkyl and alkoxy groups and the alkylgroups present within the other groups mentioned may contain 1 to 4carbon atoms unless otherwise stated,

their tautomers, their diastereomers, their enantiomers, mixturesthereof and the salts thereof.

Preferred compounds of the above general formula I are those wherein

R denotes an unbranched C₁₋₃-alkyl group which may be substituted in theω-position

by a C₅₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group,

by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-ylgroup, whilst the latter two groups may be substituted in the carbonskeleton by a phenyl, pyridinyl or diazinyl group,

by a 5-membered heteroaromatic ring linked via a carbon atom andcontaining a nitrogen, oxygen or sulphur atom or two nitrogen atoms,wherein a nitrogen of an imino group may be substituted by an alkylgroup,

or may be substituted by a pyridinyl group,

whilst a 1,4-butadienylene group may be attached both to the 5-memberedheteroaromatic monocyclic rings and to the pyridinyl group, in each casevia two adjacent carbon atoms, and the bicyclic heteroaromatic ringsthus formed may also be bound via a carbon atom of the 1,4-butadienylenegroup,

or an unbranched C₁₋₄-alkylamino group optionally substituted at thenitrogen atom by a methyl or ethyl group, which may be substituted inthe ω-position

by a C₅₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2(1H)-oxoquinolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,

by a 5-membered heteroaromatic ring linked via a carbon atom andcontaining a nitrogen, oxygen or sulphur atom or two nitrogen atoms,whilst a nitrogen atom of an imino group may be substituted by an alkylgroup,

or by a pyridinyl group,

whilst a 1,4-butadienylene group may be attached both to the 5-memberedheteroaromatic monocyclic rings and to the pyridinyl group, in each casevia two adjacent carbon atoms, and the bicyclic heteroaromatic ringsthus formed may also be bound via a carbon atom of the 1,4-butadienylenegroup,

whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbeforefor the substitution of the alkyl and alkylamino groups in theω-position as well as optionally partially hydrogenated mono- andbicyclic heteroaromatic rings may additionally be mono- or disubstitutedin the carbon skeleton by fluorine, chlorine or bromine atoms or byalkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino,propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst thesubstituents may be the same or different,

or the group of formula

 wherein

p denotes the number 1 or 2,

o denotes the number 2 or, if Y¹ and Y² are not simultaneously nitrogenatoms, it may also denote the number 1,

Y¹ denotes the nitrogen atom if R⁵ denotes a free pair of electrons, orthe carbon atom,

Y² denotes the nitrogen atom or the group >CH—,

R⁵ denotes a free pair of electrons if Y¹ denotes the nitrogen atom or,if Y¹ denotes the carbon atom, R⁵ denotes a hydrogen atom, a C₁₋₃-alkylgroup, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl oraminocarbonylamino group or a phenylmethyl or phenyl group optionallysubstituted at the aromatic moiety by a fluorine, chlorine or bromineatom or by a methyl, methoxy, ethoxy, trifluoromethyl, hydroxy, amino oracetylamino group,

R⁶ denotes the hydrogen atom or, if Y¹ is not a nitrogen atom, R⁶together with R⁵ may also denote an additional bond,

R⁷ denotes the hydrogen atom or, provided that Y¹ is not a nitrogen atomand R⁵ and R⁶ together denote an additional bond, R⁷ together with R^(N)may also denote the 1,4-butadienylene group,

R^(N) denotes the hydrogen atom or a C₁₋₃-alkyl group, which may bemonosubstituted in the ω-position

by a C₅₋₇-cycloalkyl group or by a 1-naphthyl, 2-naphthyl, hydroxy,alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl,pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl,methylaminocarbonyl, acetylamino, cyano, aminocarbonylamino oralkylaminocarbonylamino group, or may be mono- or disubstituted byphenyl, pyridinyl or diazinyl groups, whilst these substituents may beidentical or different,

a cyclohexyl, phenyl, pyridinyl, cyano, amino, benzoylamino,aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl,aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino,N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino,N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino,[N-phenyl(alkylamino)]carbonylamino,N-(phenylaminocarbonyl)-N-alkylamino,N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino,phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino,N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino,N-(aminocarbonylaminocarbonyl)-N-phenylamino,N-(pyridinyl)-N-(aminocarbonyl)amino,N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino,diazinylamino or 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinylgroup,

a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza,oxaza, thiaza, thiadiaza or S,S-dioxidothiadiaza heterocycle,

whilst the above-mentioned heterocycles may be linked via a carbon ornitrogen atom and

may contain one or two carbonyl groups adjacent to a nitrogen atom,

may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl,hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl,phenylmethyl or phenyl group,

may be substituted at one or two carbon atoms by a methyl, phenyl,phenylmethyl, naphthyl, biphenylyl, thienyl, pyridinyl or diazinylgroup, wherein the substituents may be identical or different,

and wherein a C₃₋₄-alkylene group may additionally be attached to theabove-mentioned heterocycles via two adjacent carbon atoms or anolefinic double bond of one of the above-mentioned heterocycles may befused to a thiophene, benzene, pyridine, quinoline or diazine ring,

or, if Y¹ is not a nitrogen atom and R⁵ and R⁶ together denote anadditional bond, R^(N) together with R⁷ may also denote a1,4-butadienylene group or,

if Y¹ denotes a carbon atom, R^(N) together with R⁵ with the inclusionof Y¹ may also denote a carbonyl group or a saturated or monounsaturated5- or 6-membered 1,3-diazaheterocycle which may contain one or twocarbonyl groups in the ring adjacent to a nitrogen atom and, if it isunsaturated, may also be benzo-fused at the double bond and may besubstituted at one of the nitrogen atoms by a methyl, aminocarbonyl,hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl,phenylmethyl or phenyl group,

whilst the phenyl, pyridinyl or diazinyl groups contained in the groupsmentioned under R^(N) and the thieno-, benzo-, pyrido- ordiazino-condensed heterocycles in the carbon skeleton may additionallybe mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms,by methyl groups, nitro, methoxy, ethoxy, methylsulphonylamino,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, hydroxy, amino, acetylamino, propionylamino,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl,methylaminocarbonylamino, acetyl, cyano or trifluoromethoxy groups,whilst the substituents may be identical or different,

and the alkyl groups contained in the above-mentioned radicals maycontain 1 to 3 carbon atoms, unless otherwise specified,

X denotes an oxygen atom or 2 hydrogen atoms,

Z denotes a methylene group or the group —NR¹— wherein

R¹ is a hydrogen atom or a methyl group,

R¹¹ denotes the hydrogen atom or a methyl or methoxycarbonyl group,

n denotes the number 1 or 2 or, if m is the number 1, n may also denote0,

m denotes the number 0 or 1,

R² denotes a phenyl, 1-naphthyl, 2-naphthyl,1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl,1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl,4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl,pyridinyl or quinolinyl group,

wherein the above-mentioned aromatic and heteroaromatic groups mayadditionally be mono-, di- or trisubstituted in the carbon skeleton byfluorine, chlorine or bromine atoms, by branched or unbranchedC₁₋₅-alkyl groups, allyl, vinyl, methoxy, ethoxy, propoxy,1-methylethoxy, dimethylaminoethoxy, trifluoromethyl, hydroxy, nitro,amino, acetylamino, propionylamino, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, acetyl, cyano, methylsulphonyloxy ortrifluoromethoxy groups, by tetrazolyl, phenyl pyridinyl, thiazolyl orfuryl groups and the substituents may be identical or different, or

A denotes a bond or the divalent group of formula

(linked to the NR³R⁴-group of general formula (I) via the carbonylgroup)

 wherein

R⁸ and R⁹ together denote an n-propylene group or

R⁸ denotes the hydrogen atom or the methyl group and

R⁹ denotes a hydrogen atom or an unbranched C₁₋₄-alkyl group which maybe substituted in the ω-position

by a hydroxy, amino, methylamino, dimethylamino, hydroxycarbonyl,aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl orpyridinyl group, wherein the phenyl and pyridinyl group may in turn besubstituted in the carbon skeleton by a fluorine, chlorine or bromineatom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino,acetylamino, aminocarbonyl or cyano group and wherein any hydroxy, aminoand guanidino groups contained in the groups given for R⁹ may besubstituted by a protecting group, e.g. the phenylmethoxycarbonyl ortert.butyloxycarbonyl group,

R³ denotes a hydrogen atom,

a C₁₋₄-alkyl group optionally substituted in the ω-position by acyclohexyl, phenyl, pyridinyl, hydroxy, amino, methylamino,dimethylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino,1-pyrrolidinyl, 1-piperidinyl or 4-(1-piperidinyl)-1-piperidinyl group,

a phenyl or pyridinyl group,

whilst the above-mentioned phenyl and pyridinyl groups may additionallybe substituted in the carbon skeleton by a fluorine, chlorine or bromineatom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino,acetylamino, aminocarbonyl or cyano group,

R⁴ denotes the hydrogen atom or a C₁₋₂-alkyl group optionallysubstituted by a phenyl or pyridinyl group

or R³ and R⁴ together with the enclosed nitrogen atom denote a group ofgeneral formula

 wherein

Y³ denotes a carbon atom or, if R¹² denotes a free pair of electrons, Y³may also be a nitrogen atom,

r denotes the number 0, 1 or 2,

q denotes the number 0, 1 or 2,

with the proviso that the sum of the numbers given for r and q is 0, 1,2 or 3,

R¹⁰ denotes a hydrogen atom, an alkyl, cycloalkyl, dialkylamino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonylamino, alkoxycarbonyl, alkoxycarbonylmethyl,carboxymethyl or carboxy group,

a phenyl, pyridinyl, diazinyl, pyridinylcarbonyl or phenylcarbonyl groupwhich may be mono- or disubstituted in the carbon skeleton by fluorine,chlorine or bromine atoms, or by methyl, ethyl, propyl, methoxy,hydroxy, ω-(dialkylamino)-alkyl, ω-(dialkylamino)hydroxyalkyl oralkanoyl groups, whilst the substituents may be identical or different,

a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, whichmay be substituted by a phenyl group or may be fused at the double bondto a benzene, pyridine or diazine ring,

a 5- to 7-membered azacycloalkyl group, a 4- to 7-membered oxaza- ordiazacycloalkyl group or a 7- to 9-membered azabicycloalkyl group,

wherein the above-mentioned mono- and bicyclic heterocycles are boundvia a nitrogen or a carbon atom and

may be substituted by a C₁₋₇-alkyl group, or by an alkanoyl,dialkylamino, phenylcarbonyl, carboxyalkanoyl, carboxyalkyl,alkoxycarbonylalkyl or alkoxycarbonyl group having 1 to 4 carbon atomsin the alkoxy moiety, alkylsulphonyl, cycloalkyl or cycloalkylalkylgroup or by an azacycloalkylcarbonyl or diazacycloalkylcarbonyl groupoptionally alkylsubstituted in the ring,

whilst the alicyclic groups contained in these substituents may comprise3 to 7 ring members and the heteroalicyclic groups may comprise 4 to 7ring members and

the above-mentioned phenylcarbonyl group may be substituted by afluorine, chlorine or bromine atom or by a methyl, methoxy,trifluoromethyl, hydroxy, amino or acetylamino group, or

R¹⁰ together with R¹² and Y³ denotes a 4- to 6-membered cycloaliphaticring in which a methylene group may be replaced by an —NH— or—N(CH₃)-group,

whilst a hydrogen atom bound to a nitrogen atom within the group R¹⁰ maybe replaced by a protecting group, e.g. the phenylmethoxycarbonyl ortert.butyloxycarbonyl group,

R¹² denotes a hydrogen atom, a C₁₋₂-alkyl group which may be substitutedin the ω-position by a phenyl, pyridinyl, amino, alkylamino,dialkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-methyl-1-piperazinylgroup,

a methoxycarbonyl or ethoxycarbonyl, cyano or aminocarbonyl group or afree pair of electrons, if Y³ denotes a nitrogen atom, and

R¹³ and R¹⁴ each denote a hydrogen atom or,

if Y³ is a carbon atom, R¹² together with R¹⁴ also denotes anothercarbon-carbon bond, wherein R¹⁰ is as hereinbefore defined and R¹³denotes a hydrogen atom, or

if Y³ is a carbon atom, R¹² together with R¹⁴ also denotes anothercarbon-carbon bond and R¹⁰ together with R¹³ and the enclosed doublebond denotes a partially hydrogenated or aromatic 5- or 6-membered mono-or bicyclic carbocycle or heterocycle, containing one or two nitrogenatoms,

whilst all the above-mentioned alkyl and alkoxy groups and the alkylgroups present within the other groups named may contain 1 to 3 carbonatoms, unless otherwise stated, and

all the above-mentioned cycloalkyl groups and the cycloalkyl groupspresent within the other groups named may contain 5 to 7 carbon atoms,unless otherwise specified,

their tautomers, their diastereomers, their enantiomers, mixturesthereof and the salts thereof.

One subgroup of particularly preferred compounds of general formula Ideserving special mention comprises those wherein

A, R², R³, R⁴, R¹¹, X, Z and m and n are defined as for the particularlypreferred compounds of general formula I hereinbefore and

R denotes an unbranched C₁₋₄-alkylamino group optionally substituted atthe nitrogen atom by a methyl or ethyl group, which may be substitutedin the ω-position

by a C₅₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2(1H)-oxoquinolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,

by a 5-membered heteroaromatic ring linked via a carbon atom andcontaining a nitrogen, oxygen or sulphur atom or two nitrogen atoms,whilst a nitrogen atom of an imino group may be substituted by an alkylgroup,

or by a pyridinyl group,

whilst a 1,4-butadienylene group may be attached both to the 5-memberedheteroaromatic monocyclic rings and also to the pyridinyl group, in eachcase via two adjacent carbon atoms, and the bicyclic heteroaromaticrings thus formed may also be bound via a carbon atom of the1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbeforefor the substitution of the alkylamino groups in the ω-position, as wellas optionally any partially hydrogenated mono- and bicyclicheteroaromatic rings, may additionally be mono- or disubstituted in thecarbon skeleton by fluorine, chlorine or bromine atoms or by alkyl,nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino,propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst thesubstituents may be identical or different,

whilst all the above-mentioned alkyl and alkoxy groups and the alkoxygroups present within the other named radicals may contain 1 to 3 carbonatoms unless otherwise stated,

their tautomers, their diastereomers, their enantiomers, mixturesthereof and the salts thereof.

Another subgroup of particularly preferred compounds of general formulaI which deserves special mention comprises those compounds wherein

R², R³, R⁴, R¹¹, X, Z and m and n are as hereinbefore defined for thefirst-mentioned particularly preferred subgroup,

R denotes an unbranched C₁₋₃-alkyl group which may be substituted in theω-position

by a C₅₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group,

by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-ylgroup, whilst the latter two groups may be substituted in the carbonskeleton by a phenyl, pyridinyl or diazinyl group,

by a 5-membered heteroaromatic ring linked via a carbon atom andcontaining a nitrogen, oxygen or sulphur atom or two nitrogen atoms,wherein a nitrogen atom of an imino group may be substituted by an alkylgroup,

or by a pyridinyl group,

whilst a 1,4-butadienylene group may be attached both to the 5-memberedheteroaromatic monocyclic rings and also to the pyridinyl group via twoadjacent carbon atoms in each case and the bicyclic heteroaromatic ringsthus formed may also be bound via a carbon atom of the 1,4-butadienylenegroup,

whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbeforefor the substitution of the alkyl groups in the ω-position as well asoptionally any partially hydrogenated mono- and bicyclic heteroaromaticrings may additionally be mono- or disubstituted in the carbon skeletonby fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy,trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl,cyano or trifluoromethoxy groups wherein the substituents may beidentical or different,

and A denotes a single bond,

whilst all the above-mentioned alkyl and alkoxy groups and the alkylgroups present within the other groups mentioned may contain 1 to 3carbon atoms unless otherwise specified,

their tautomers, their diastereomers, their enantiomers and their salts.

More particularly preferred compounds of the above general formula I arethose wherein

R denotes an unbranched C₁₋₃-alkyl group which may be substituted in theω-position

by a C₅₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group, whilst the above-mentioned aromatic groups mayadditionally be substituted by a fluorine, chlorine or bromine atom orby a methyl, methoxy, amino or acetylamino group,

by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl orisoquinolinyl group,

or an unbranched C₁₋₄-alkylamino group which is optionally additionallysubstituted at the nitrogen atom by a methyl or ethyl group and whichmay be substituted in the ω-position

by a C₅₋₇-cycloalkyl group,

by a phenyl group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, or by methyl, nitro, methoxy,trifluoromethyl, hydroxy, amino or acetylamino groups, whilst thesubstituents may be identical or different,

by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl orisoquinolinyl group,

or the group of formula

 wherein

p denotes the number 1 or 2,

o denotes the number 2 or, if Y¹ and Y² are not simultaneously nitrogenatoms, it may also denote the number 1,

Y¹ denotes the nitrogen atom if R⁵ denotes a free pair of electrons, orthe carbon atom,

Y² denotes the nitrogen atom or the group >CH—,

R⁵ denotes a free pair of electrons, if Y¹ denotes the nitrogen atom or,if Y¹ denotes the carbon atom, R⁵ may denote the hydrogen atom, aC₁₋₂-alkyl group or the cyano or phenyl group,

R⁶ denotes the hydrogen atom or, provided that Y¹ is not a nitrogenatom, R⁶ together with R⁵ may also denote an additional bond,

R⁷ denotes the hydrogen atom or, provided that Y¹ is not a nitrogen atomand R⁵ and R⁶ together denote an additional bond, R⁷ together with R^(N)may also denote the 1,4-butadienylene group,

R^(N) denotes the hydrogen atom or a C₁₋₃-alkyl group, which may besubstituted in the ω-position

by one or two phenyl or pyridinyl groups, wherein the substituents maybe identical or different,

or by a hydroxy or methoxy group,

a phenyl group which may be mono- or disubstituted by fluorine, chlorineor bromine atoms or by methyl groups, nitro, methoxy, ethoxy,trifluoromethyl, hydroxy or cyano groups, whilst the substituents may beidentical or different, or a phenyl group substituted by amethylenedioxy group,

a 2-pyridinyl or 4-pyridinyl group,

an amino, benzoylamino, aminocarbonyl, methylaminocarbonyl,methoxycarbonyl, ethoxycarbonyl, aminocarbonylamino,methylaminocarbonylamino, N-(aminocarbonyl)-N-methylamino,N-(methylaminocarbonyl)-N-methylamino,N-(aminocarbonyl)-N-(4-fluorophenyl)amino,N-(methylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino,[N-phenyl(methylamino)]carbonylamino,N-(phenylaminocarbonyl)-N-methylamino,N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino,N-(aminocarbonyl)-N-phenylamino group or a phenylamino group optionallysubstituted in the phenyl ring by an aminocarbonylamino ormethylsulphonylamino group,

a 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, a1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxobenzimidazol-1-yl,1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl, 1H-indol-3-yl,2,4(1H,3H)-dioxoquinazolin-3-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl,1,3(2H)-dioxo-1H-isoindol-2-yl, 1H-benzimidazol-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 2(3H)-oxobenzoxazol-3-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-d]pyrimidin-3-yl,2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl,3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidin-3-yl,2(1H)-oxoquinolin-3-yl, 3,4-dihydro-2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl,1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl,2,5-dioxo-4-phenylimidazolidin-1-yl,2,5-dioxo-4-(phenylmethyl)-imidazolidin-1-yl,3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl,1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl,1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl,1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,4-phenyl-2(1H)-oxopyrimidin-1-yl,4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl,3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl,3,4-dihydro-2[1H]-oxopyrido[4,3-d]pyrimidin-3-yl or2,3-dihydro-4(1H)-oxoquinazolin-3-yl group,

wherein the above-mentioned mono- and bicyclic heterocycles may besubstituted at one of the nitrogen atoms by a methoxycarbonylmethylgroup and/or

the above-mentioned mono- and bicyclic heterocycles may be mono-, di- ortrisubstituted in the carbon skeleton and/or at the phenyl groupscontained in these groups by fluorine, chlorine or bromine atoms, or bymethyl, trifluoromethyl, methoxy, hydroxy, amino, nitro, phenyl,phenylmethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,methylaminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl,(1-piperidinyl)carbonyl or (4-methyl-1-piperazinyl)carbonyl groupswherein the substituents may be identical or different and multiplesubstitution with the last three substituents is ruled out,

or, provided that Y¹ is not a nitrogen atom and R⁵ and R⁶ togetherdenote an additional bond, R^(N) together with R⁷ also denotes the1,4-butadienylene group,

or, provided that Y¹ denotes a carbon atom, R^(N) together with R⁵ withthe inclusion of Y¹ may also denote a carbonyl group or saturated ormonounsaturated five- or six-membered 1,3-diaza-heterocycle,

which may contain a carbonyl group in the ring, adjacent to a nitrogenatom,

may be substituted by a phenyl group at one of the nitrogen atoms

and, if it is unsaturated, may also be benzo-condensed at the doublebond,

X denotes an oxygen atom or 2 hydrogen atoms,

Z denotes a methylene group or the group —NR¹, wherein

R¹ denotes a hydrogen atom or a methyl group,

R¹¹ denotes a hydrogen atom, a methoxycarbonyl, ethoxycarbonyl or methylgroup,

n denotes the number 1 and m denotes the number 0 or

n denotes the number 0 and m denotes the number 1,

R² denotes a phenyl, 1-naphthyl, 2-naphthyl,1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl,1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 2-thienyl, 3-thienyl,thiazolyl or alkylthiazolyl group having 1 to 3 carbon atoms in thealkyl moiety, a pyridinyl or quinolinyl group,

wherein the above-mentioned phenyl and naphthyl groups may be mono-, di-or trisubstituted by fluorine, chlorine or bromine atoms or by branchedor unbranched C₁₋₅-alkyl groups, by C₁₋₃-alkoxy groups, by vinyl, allyl,trifluoromethyl, methylsulphonyloxy, 2-(dimethylamino)ethoxy, hydroxy,cyano, nitro or amino groups, by tetrazolyl, phenyl, pyridinyl,thiazolyl or furyl groups and the substituents may be identical ordifferent, and multiple substitution with the last five substituents isruled out,

A denotes a bond or the divalent group of formula

(linked to the group —NR³R⁴ of formula (I) via the carbonyl group)

 wherein

R⁸ and R⁹ together denote an n-propylene group or

R⁸ denotes the hydrogen atom or the methyl group and

R⁹ denotes the hydrogen atom or an unbranched C₁₋₄-alkyl group,

which may be substituted in the ω-position by an amino, methylamino,dimethylamino, aminoiminomethylamino or aminocarbonylamino group, whilstin the above-mentioned substituents a hydrogen atom bound to a nitrogenatom may be replaced by a protecting group, e.g. thephenylmethoxycarbonyl or tert.butyloxycarbonyl group,

R³ denotes a hydrogen atom or

a C₁₋₄-alkyl group optionally substituted in the ω-position by an amino,methylamino, dimethylamino- or 4-(1-piperidinyl)-1-piperidinyl group,

R⁴ denotes a hydrogen atom or a methyl or ethyl group

or R³ and R⁴ together with the enclosed nitrogen atom denote a group ofgeneral formula

 wherein

Y³ denotes the carbon atom or, if R¹² denotes a free pair of electrons,Y³ may also denote a nitrogen atom,

r denotes the number 1,

q denotes the number 1,

R¹⁰ denotes the hydrogen atom, an alkyl, dialkylamino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylamino,alkoxycarbonyl, alkoxycarbonylmethyl, carboxymethyl or carboxy group ora cycloalkyl group having 4 to 7 carbon atoms in the ring,

a benzoyl, pyridinylcarbonyl, phenyl, pyridinyl or diazinyl group, eachof which may be substituted in the carbon skeleton by a fluorine,chlorine or bromine atom, or by an acetyl, methyl, ethyl or methoxygroup, or by a dimethylaminoalkyl group having 1 to 4 carbon atoms inthe alkyl moiety optionally hydroxysubstituted in the alkyl moiety,

a 1,3-dihydro-2-oxo-2H-imidazolyl group bound via a nitrogen atom, whichmay be fused to a benzene or pyridine ring at the double bond,

a 1-pyrrolidinyl, 1-piperidinyl, 4-(dimethylamino)-1-piperidinyl,4-piperidinyl or 4-morpholinyl group, wherein the nitrogen atom of the4-piperidinyl group may be substituted by an alkanoyl- or alkyl groupeach having 1 to 7 carbon atoms or by a benzoyl, methylsulphonyl,3-carboxy-propionyl, cyclopropylmethyl, alkoxycarbonylmethyl orcarboxymethyl group or by a protecting group, e.g. thephenylmethoxycarbonyl or tert.butyloxycarbonyl group, or it mayrepresent a hexahydro-1H-1-azepinyl,8-methyl-8-azabicyclo[3,2,1]oct-3-yl, 4-alkyl-1-piperazinyl,hexahydro-4-alkyl-1H-1,4-diazepin-1-yl, 1-alkyl-4-piperidinylcarbonyl or4-alkyl-1-piperazinylcarbonyl group, or

R¹⁰ together with R¹² and Y³ denotes a 5-membered cycloaliphatic ring inwhich a methylene group may be replaced by an —NH— or —N(CH₃)— group,

R¹² denotes a hydrogen atom, a C₁₋₂-alkyl group which may be substitutedin the ω-position by a 1-pyrrolidinyl, 1-piperidinyl or4-methyl-1-piperazinyl group,

a methoxycarbonyl or ethoxycarbonyl or a cyano group,

a free pair of electrons if Y³ denotes a nitrogen atom, and

R¹³ and R¹⁴ each denote a hydrogen atom or,

provided that Y³ is a carbon atom, R¹² together with R¹⁴ may also denotean additional carbon-carbon bond, wherein R¹⁰ is as hereinbefore definedand R¹³ denotes a hydrogen atom or,

provided that Y³ is a carbon atom, R¹² together with R¹⁴ may also denotean additional carbon-carbon bond and R¹⁰ together with R¹³ and theenclosed double bond denotes an indole group fused on via the 5-memberedring,

whilst all the above-mentioned alkyl groups and the alkyl groups presentwithin the other named groups may contain 1 to 3 carbon atoms, unlessotherwise specified,

their tautomers, their diastereomers, their enantiomers and their salts.

A subgroup of most particularly preferred compounds of general formula Ideserving special mention comprises those wherein

A, R², R³, R⁴, R¹¹, X, Z and m and n are as hereinbefore defined for themost particularly preferred compounds of general formula I and

R denotes an unbranched C₁₋₄-alkylamino group optionally substituted atthe nitrogen atom by a methyl or ethyl group, which may be substitutedin the ω-position

by a C₅₋₇-cycloalkyl group,

by a phenyl group, which may be mono- or disubstituted by fluorine,chlorine or bromine atoms or by methyl, nitro, methoxy, trifluoromethyl,hydroxy, amino or acetylamino groups, wherein the substituents may beidentical or different, or

by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl orisoquinolinyl group,

their tautomers, their diastereomers, their enantiomers, mixturesthereof and salts thereof.

Another subgroup of most particularly preferred compounds of generalformula I deserving special mention comprises those wherein

R², R³, R⁴, R¹¹, X, Z and m and n are as defined hereinbefore for thefirst-mentioned particularly preferred subgroup,

R denotes an unbranched C₁₋₃-alkyl group which may be substituted in theω-position

by a C₅₋₇-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or(4-biphenylyl) group, whilst the above-mentioned aromatic groups may besubstituted by a fluorine, chlorine or bromine atom or by a methyl,methoxy, amino or acetylamino group,

or by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl- orisoquinolinyl group,

and A denotes a single bond,

their tautomers, their diastereomers, their enantiomers, mixturesthereof and the salts thereof.

The following are mentioned as examples of most particularly preferredcompounds:

(1)1-[N²-[N-[[[2-(2-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(2)1-[N²-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(3)1-[N²-[N-[[[2-(2,5-Dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(4)1-[N²-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazine

(5)1-[N²-[N-[[[2-(2,3-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(6)1-[N²-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(1-methyl-4-piperidinyl)-piperazine

(7)1-[N²-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-piperidinyl)-piperazine

(8)1-[N²-[N-[[[2-(3,4-dihydroxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine

(9)1-[N²-[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(10)1-[N²-[N-[4-(3-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(11)1-[N²-[N-[[(2-Phenylethyl)amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(12)1-[N²-[N-[[[2-(4-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(13)1-[N²-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3-(1-naphthyl)-D-alanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(14)1-[N²-[N-[[[2-(3-Hydroxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(15)1-[N²-[N-[3-(3-Methoxyphenyl)-1-oxopropyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(16)1-[N²-[N-[[[2-(3-Methoxyphenyl)ethyl]methylamino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(17)1-[N²-[N-(4-Phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(18)1-[N²-[N-[4-(2-Methylphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(19)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(20)1-[N²-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dichloro-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine

(21)1-[N²-[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidin

(22)1-[N²-[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(23)1-[N²-[N-(4-Phenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(24)1-[N²-[N-[4-(4-Fluorophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(25)1-[N²-[N-[4,4-Diphenyl-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(26)1-[N²-[N-[4-Cyclohexyl-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(27) 1-[N²-[N-[4-(4-Acetylaminophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(28)1-[N²-[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dichloro-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine

(29)1-[N²-[N-[4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine

(30)1-[N²-[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(31) 1-[N²-[N-[4-(3,4-Methylenedioxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(32)1-[N²-[N-(4-Methyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(33)1-[N²-[N-[4-(2-Hydroxyethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(34)1-[N²-[N-[4-(4-Pyridinyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(35)1-[N²-[N-[4-(2-Pyridinyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(36)1-[N²-[N-[4-(Diphenylmethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(37)1-[N²-[N-[4-(Phenylmethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(38)1-[N²-[N-[4-(4-Nitrophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(39)1-[N²-[N-[4-(Ethoxycarbonyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(40)1-[N²-[N-[[[3-(2-Methoxyphenyl)propyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(41)1-[N²-[N-[[[2-(3-Bromophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(42)1-[N²-[N-[[[2-(3-Nitrophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(43)1-[N²-[N-[[[2-(3-Acetylaminophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(44)1-[N²-[N-[[[2-(3-Bromophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(45)1-[N²-[N-[(1,2,4,5-Tetrahydro-3H-3-benzazepin-3-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(46)1-[N²-[N-[[[2-[3-(Trifluoromethyl)phenyl]ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(47)1-[N²-[N-[[[2-(3-Fluorophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(48)1-[N²-[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-fluorophenyl)-piperazine

(49)1-[N²-[4-Amino-3,5-dibromo-N-[[(2-phenylethyl)amino]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(50)1-[N²-[N-[4-(2-Methoxyphenyl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(51)1-[N²-[N-[4-(3-Methoxyphenyl)-1,2,5,6-tetrahydro-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(52)1-[N²-[N-[4-(2-Methoxyphenyl)-1,2,5,6-tetrahydro-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(53)1-[N²-[N-[(4-Biphenylyl)acetyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(54)1-[N²-[N-[4-(4-Bromophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(55)1-[N²-[N-[4-(1H-Indol-3-yl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(56)1-[N²-[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(57)1-[N²-[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(58)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(59)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(60)1-[N²-[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(61)1-[N²-[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(62)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(2-pyridinyl)-piperazine

(63)1-[N²-[N-[[[2-(2-Cyclohexyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(64)1-[N²-[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(65)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(66)1-[N²-[N-[4-(Aminocarbonyl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(67)1-[N²-[N-[[[2-(1H-Indol-3-yl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(68)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-methoxyphenyl)-piperazine

(69)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-pyridinyl)-piperazine

(70)1-[N²-[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-methoxyphenyl)-piperazine

(71)1-[N²-[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-pyridinyl)-piperazine

(72)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D,L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(73)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D,L-phenylalanyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(74)1-[N²-[N-[4-(2,3-Dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(75)1-[N²-[N-[4-(3,5-Dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(76)1-[N²-[N-[4-(2-Cyanphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(77)1-[N²-[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D,L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(78)1-[N²-[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D,L-phenylalanyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(79)1-[N²-[N-[4-[4-Chloro-3-(trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(80)1-[N²-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(81)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(82)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(83)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(84)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-[1-(1-methylethyl)-4-piperidinyl]-piperidine

(85)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-phenylpiperazine

(86)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(87)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(88)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5,6-dichloro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(89)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-3-(methoxycarbonylmethyl)-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(90)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine

(91)1-[4-Amino-3,5-dibromo-N-[[4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(92)1-[4-Amino-3,5-dibromo-N-[[4-(benzoylamino))-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(93)1-[4-Amino-3,5-dibromo-N-[[4-(aminocarbonyl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(94)1-[4-Amino-3,5-dibromo-N-[(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(95)1-[3,5-Dibromo-N-[[4-(benzoylamino)-1-piperidinyl]caronyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(96)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-6-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(97)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(98)3,5-Dibromo-N²-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosinamide

(99)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-methylpiperazine

(100)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)piperazine

(101)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperazine

(102)3,5-Dibromo-N²-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N,N-diethyl-D-tyrosinamide

(103)3,5-Dibromo-N²-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[(4-(dimethylamino)butyl]-D-tyrosinamide

(104)1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(105)1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(106)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]piperazine

(107)1-[4-Amino-3,5-dibromo-N-[(4-cyan-4-phenyl-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(108)1-[3,5-Dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(109)1-[3,5-Dibromo-N-[(4-cyan-4-phenyl-1-piperidinyl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(110)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine

(111)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyrimidinyl)-piperazine

(112)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-pyridinyl)-piperazine

(113)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4(pyrazinyl)-piperazine

(114)1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine

(115)1-[3,5-Dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-tyrosyl]-4-(2-pyridinyl)-piperazine

(116)1-[4-Amino-3,5-dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(117)1-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(118)1-[3,5-Dibromo-N-[[4-(aminocarbonyl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(119)1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(pyrazinyl)-piperazine

(120)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-pyrimidinyl)-piperazine

(121)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxo-imidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(122)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(123)cis-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(124)trans-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(125)1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(4-pyridinyl)-piperazine

(126)1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(4-pyridinyl)-piperidine

(127)1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(1-piperidinyl)-piperidine

(128)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine

(129)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(pyrazinyl)-piperazine

(130)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-methoxyphenyl)-piperazine

(131)1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(2-methoxyphenyl)-piperazine

(132)1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine

(133)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-methoxyphenyl)-piperazine

(134)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(135)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(136)1-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(137)1-[4-Amino-N-[[4-(1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(138)1-[4-Amino-3,5-dibromo-N-[[4-(1,3(2H)-dioxo-1H-isoindol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(139)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(140)1-[N²-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(141)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(142)1-[N²-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(143)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(144)1-[3,5-Dibromo-N-[(4′(3′H)-oxospiro[piperidine-4,2′(1′H)-quinazolin]-1-yl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(145)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(146)1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-3-(4-pyridinyl)alanyl]-4-(4-pyridinyl)-piperazine

(147)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(148)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(149)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(150)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-(methoxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(151)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(152)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxomidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(153)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(154)1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(155)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine

(156)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-fluorophenyl)-piperazine

(157)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-fluorophenyl)-piperazine

(158)1-[4-Amino-3,5-dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(159)1-(4-Amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(160)1-[3,5-Dibromo-N-[[4-(aminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

161)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-4-pyrimidinyl)-piperazine

(162)1-[3,5-Dibromo-N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(163)1-[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(164)1-[4-Amino-3,5-dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(165)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine

(166)1-[3,5-Dibromo-N-[[4-(methylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(167)1-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)-methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(168)1-[N²-[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine

(169)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine

(170)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine

(171)1-[3,5-Dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(172)1-[3,5-Dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(173)1-[2,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine

(174)1-[2,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine

(175)1-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(176)1-[N²-[3,5-Dibromo-N-[[4-(methylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine

(177)1-[N²-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine

(178)1-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)-methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(179)1-[N²-[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(180)1-[N²-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine

(181)1-[N²-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)methylaminol-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(182)1-[N²-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)amino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(183)1-[N²-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(184)1-[N²-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(185)1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(186)1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(187)1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(188)1-[N²-[N-[[4-[2(3H)-Oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(189)1-[4-Amino-3,5-dibromo-N-[[4-(1H-indol-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(190)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(191)1-[N²-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(192)1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(193)1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperazine

(194)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-cyclohexyl-4-piperidinyl)-piperazine

(195)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine

(196)1-[N²-[N-[[4-(2-Cyanophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine

(197)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine

(198)1-[N²-[N-[[4-(2-Cyanophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine

(199)1-[3,5-Dichloro-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(200)1-[3,5-Dichloro-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(201)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(202)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-morpholinyl)-piperidine

(203)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(ethoxycarbonyl)-piperidine

(204)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(dimethylamino)-piperidine

(205)1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(206)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-pyrrolidinyl)-piperidine

(207)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(methoxycarbonyl)-4-phenylpiperidine

(208)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(209)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine

(210)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine

(211)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hydroxycarbonyl)-piperidine

(212)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶,N⁶-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine

(213)1-[N²-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine

(214)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperazine

(215)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidine

(216)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-piperidine

(217)1-[N²-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(218)1-[N²-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(219)(R)-1-[2-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine(220)(R)-1-[2-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]amino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine

(221)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N⁶,N⁶-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine

(222)3,5-Dibromo-N²-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[(2-[4-(1-piperidinyl)-1-piperidinyl]ethyl]-D-tyrosinamide

(223)1-[3,5-Dibromo-N-[[4-[5-[(4-morpholinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(224)1-[3,5-Dibromo-N-[[4-[5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(225)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(226)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(227)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquiazolin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(228)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(229)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(230)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(231)1-[4-Amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(232)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine

(233)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(234)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(235)1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine

(236)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(237)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine

(238)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(239)1-(3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(240)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(241)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(242)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(243)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(244)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine

(245)(R)-1-[2-[N-[[4-(3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]-3-(4-amino-3,5-dibromophenyl)-propyl]-4-(1-piperidinyl)-piperidine

(246)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(247)1-[N²-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine

(248)1-[N²-[3,5-Dibromo-N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(249)1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-[(1-piperidinyl)methyl]-piperidine

(250)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(251)1-[N²-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(252)1-[N²-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(253)1-[N²-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(254)1-[N²-[3,5-Dibromo-N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(255)1-[N²-[3,5-Dibromo-N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(256)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(257)1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-glycyl]-4-(4-pyridinyl)-piperazine

(258)1-[4-Amino-3,5-dibromo-N-[[4-(benzoylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(259)1-[4-Amino-3,5-dibromo-N-[[4-(benzoylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(260)1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-β-alanyl]-4-(4-pyridinyl)-piperazine

(261)1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N-methylglycyl]-4-(4-pyridinyl)-piperazine

(262)1-[4-Amino-3,5-dibromo-N-[[4-[N-(phenylaminocarbonyl)-phenylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(263)1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-[3-(2-thienyl)-D-alanyl]-4-(1-piperidinyl)-piperidine

(264)4-Amino-3,5-dibromo-N²-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methyl-N-[3-(4-methyl-1-piperazinyl)propyl]-D-phenylalaninamide

(265)1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-glycyl]-4-(1-piperidinyl)-piperidine

(266)1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-alanyl]-4-(4-pyridinyl)-piperazine

(267)1-[N²-[4-Amino-3,5-dibromo-N-[[4-[N-(methylaminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine

(268)1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-alanyl]-4-(1-piperidinyl)-piperidine

(269)1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(270)1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(271)1-[N²-[4-Amino-3,5-dibromo-N-[[4-[N-(methylaminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine

(272)1-[N²-[[4-(1,3-Dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-1-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-piperidinyl)-piperidine

(273)1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N-methylglycyl]-4-(1-piperidinyl)-piperidine

(274)1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinoxalin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(275)1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinoxalin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(276)1-[4-Amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-(4-fluorophenyl)amino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(277)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(278)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine

(279)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-dimethylamino)propyl]-piperidine

(280)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(281)1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tryptyl]-4-(1-piperidinyl)-piperidine

(282)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)l-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(283)1-[N²-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine

(284)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(285)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine

(286)3,5-Dibromo-N²-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[2-(4-methyl-1-piperazinyl)ethyl]-D-tyrosinamide

(287)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(288)1-[3,5-Dibromo-N-[[4-(7,9-dihydro-6,8-dioxo-1H-purin-9-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(289)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(290)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine

(291)(R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(4-pyridinyl)-piperidine

(292)(R)-1-[3-(3,5-Dibromo-4-hydroxyphenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine

(293)1-[N⁶-Acetyl-N²-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(294)1-[N²-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N⁶,N⁶-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine

(295)1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶,N⁶-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine

(296)(R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2((1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine

(297)(R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine

(298)(R)-1-[3-(4-Amino-3-bromophenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine

(299)(R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine

(300)(R)-1-[3-(4-Amino-3-bromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine

(301)(R)-1-[3-(3,5-Dibromo-4-hydroxyphenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine

(302)(R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine

(303)1-[4-Amino-N-[[4-[2-(aminocarbonylamino)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(304)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(305)1-[4-Amino-N-[[4-[2-(methylsulphonylamino)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(306)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(307)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(308)1-[4-Amino-3,5-dibromo-N-[[4-[3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(309)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(310)1-[4-Amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(311)1-[4-Amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(312)1-[4-Amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(313)1-[4-Amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(314)1-[4-Amino-3,5-dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(315)1-[4-Amino-3,5-dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(316)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(317)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine

(318)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine

(319)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-fluorophenyl)-piperazine

(320)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-fluorophenyl)-piperazine

(321)1-[3,5-Dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(322)trans-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(323)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-6,7-dimethoxy-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(324)1-[N-[[4-(5-Chloro-3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(325)1-[3,5-Dibromo-N-[[3-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-pyrrolidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(326)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(327)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(328)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-8-methoxy-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(329)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(330)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(331)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(332)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(333)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(334)1-[N-[[4-(1,3-dihydro-4-[3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-3-(4-pyridinyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine

(335)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(336)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(337)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(338)(R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine

(339)(R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine

(340)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine

(341)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1methyl-4-piperidinyl)-piperidine

(342)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(343)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine

(344)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(345)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(346)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(347)1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(348)1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(349)1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(350)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(351)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(352)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(353)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(354)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-tyrosyl]-4-(4-pyridinyl)-piperidine

(355)1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(356)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine

(357)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(358)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine

(359)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(360)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(361)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(362)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(363)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(364)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(365)1-[N2-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(366)1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine

(367) 1-[4-Amino-3,5dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine

(368)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine

(369)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[4-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperazine

(370)1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine

(371)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine

(372)4-(1-Acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-piperidine

(373)1-[4-Amino-N-[[4-(6-bromo-3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(374)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(375)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(376)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(377)1-[4-Amino-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(378)1-[N²-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

(379)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine

(380)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine

(381)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine

(382)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine

(383)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine

(384)1-[3,5-Dibromo-N-[[4-[1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(385)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine

(386)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(387)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine

(388)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine

(389)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(phenylaminocarbonylamino)-piperidine

(390)1-[4-Amino-3,5-dibromo-N-[[4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(391)1-[3,5-Dibromo-N-[[4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(392)1-[3,5-Dibromo-N-[[4-[4-phenyl-2(1H)-oxopyrimidin-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(393)4-Cyano-1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperidine

(394)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyrimidinyl)-piperazine

(395)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyrimidinyl)-piperazine

(396)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine

(397)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine

(398)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(399)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine

(400)1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(401)2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole

(402)1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(403)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(404)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-ethylphenyl)-piperazine

(405)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine

(406)1-[3,5-Dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(407)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(408)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazine

(409)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazine

(410)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorobenzoyl)-piperidine

(411)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-cyano-4-phenylpiperidine

(412)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperidine

(413)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(hexahydro-1-methyl-4-pyridinyl)carbonyl]-piperazine

(414)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine

(415)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine

(416)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine

(417)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine

(418)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine

(419)1-[N-[4-[[1,3-Dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine

(420)1-[3,5-Dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(421)1-[3,5-Dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(422)1-[3,5-Dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(423)1-[3,5-Dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(424)1-[4-Amino-3,5-dibromo-N-[[4-[7-(methylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(425)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-morpholinyl)-piperidine

(426)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(dimethylamino)-piperidine

(427)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-pyrrolidinyl)-piperidine

(428)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-morpholinyl)-piperidine

(429)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(dimethylamino)-piperidine

(430)1-[4-Amino-3,5-dibromo-N-[[4-[7-[(4-methyl-1-piperazinyl)carbonyl]-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(431)1-[4-Amino-3,5-dibromo-N-[[4-(2,5-dioxo-4-phenylimidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(432)1-[3,5-Dibromo-N-[[4-(2,5-dioxo-4-phenylimidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(433)1-[4-Amino-3,5-dibromo-N-[[4-[2,5-dioxo-4-(phenylmethyl)-imidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(434)1-[3,5-Dibromo-N-[[4-[2,5-dioxo-4-(phenylmethyl)imidazolidin-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(435)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidine

(436)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine

(437)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(438)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-cyclohexylpiperazine

(439)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cyclohexylpiperazine

(440)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(441)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(442)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine

(443)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine

(444)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(445)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine

(446)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine

(447)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine

(448)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(449)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(450)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-N-methyl-D-tyrosyl]-4-(4-pyridinyl)-piperidine

(451)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine

(452)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine

(453)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperazine

(454)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(455)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(456)1-[3,4-Dichloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(457)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine

(458)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(459)(R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(460)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cycloheptylpiperazine

(461)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cyclopentylpiperazine

(462)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-4-methoxy-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(463)1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine

(464)1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(465)1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(466)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(467)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(468)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(469)1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(470)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(471)1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(4-biphenylyl)-D,L-alanyl]-4-(1-piperidinyl)-piperidine

(472)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-biphenylyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(473)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(474)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(475)1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(476)1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(477)1-[3,4-Dichloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine

(478)1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(479)1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(480)1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine

(481)1-[4-Amino-3,5-dibromo-N-[[4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(482)1-[4-Amino-3,5-dibromo-N-[[4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(483)1-[4-Amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(484)1-[4-Amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(485)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-benzoyl-4-piperidinyl)-piperidine

(486)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine

(487)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(3-carboxy-1-oxopropyl)-4-piperidinyl]-piperidine

(488)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine

(489)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidine

(490)1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine

(491)1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(492)1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine

(493)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine

(494)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(carboxymethyl)-4-piperidinyl]-piperidine

(495)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(496)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(4-pyridinyl)carbonyl]-piperazine

(497)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)piperidine

(498)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine

(499)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine

(500)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazine

(501)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)piperidine

(502)1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine

(503)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine

(504)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine

(505)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)carbonyl]-piperidine

(506)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(507)1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(508)(R,S)-1-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(509)1-[4-Amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine

(510)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine

(511)1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(512)1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(513)1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine

(514)1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine

(515)1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine

(516)1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine

(517)1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine

(518)1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

(519)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(520)1-[4-Amino-N-[[4-[4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(521)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine

(522)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine

(523)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-(methylsulphonyloxy)-D-phenylalanyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine

(524)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine

(525)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidine

(526)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine

(527)1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-(2-methyl-4-thiazolyl)-D,L-alanyl]-4-(1-piperidinyl)-piperidine

(528)1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-(2-methyl-4-thiazolyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine

(529)(R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(530)(R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(531)(R,S)-1-[2-[(3-Methoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(532)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(533)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(534)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(535)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperazinyl)-piperidine

(536)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(537)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine

(538)(R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(539)(R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine

(540)(R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(541)(R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine

(542)(R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(543)(R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(544)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(545)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine

(546)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(547)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(548)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine

(549)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(550)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-[2-(dimethylamino)ethoxy]phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine

(551)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazalin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperidine

(552)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine

(553)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine

(554)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine

(555)1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine

(556)1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine

(557)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine

(558)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(4-pyridinyl)carbonyl]-piperazine

(559)1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(560)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine

(561)1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine

(562)1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine

(563)1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine

(564)1-[4-Amino-N-[(4-amino-1-piperidinyl)carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(565)1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine

(566)1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine

(567)1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine

(568)1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine

(569)1-[3,5-Dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)-piperidine

(570)1-[N²-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine

(571)1-[N²-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine

(572)1-[N²-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine

(573)1-[N²-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine

(574)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(575)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(576)1-[N²-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine

(577)1-[N²-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine

(578)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(579)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(580)1-[N²-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine

(581)1-[N²-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine

(582)1-[4-Amino-3,5-dibromo-N-[[4-(2,3-dihydro-4(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(583)1-[N²-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine

(584)1-[N²-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine

(585)1-[4-Amino-N-[[4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine

(586)1-[4-Amino-N-[[4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine

(587)1-[N²-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine

(588)1-[N²-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine

(589)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(590)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(591)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3,4-difluoro-5-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(592)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3,4-difluoro-5-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(593)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonyl)-piperidine

(594)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonylmethyl)-piperidine

(595)(R,S)-2-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-6-methyl-2,6-diazaspiro[3,4]octane

(596)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(hydroxycarbonylmethyl)-piperidine

(597)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(598)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(599)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(600)(R,S)-1-[4-[4-(Aminocarbonylamino)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(601)(R,S)-1-[4-[4-(Aminocarbonylamino)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(602)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methoxyphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(603)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-carboxypiperidine

(604)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(605)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-fluor-3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(607)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-fluor-3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(607)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine

(608)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine

(609)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(610)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine

(611)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine

(612)(R,S)-1-[2-[(4-Amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(613)1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(614)1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(615)1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(cyclopentyl)-piperazine

(616)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-methylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(617)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine

(618)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine

(619)1-[3-Bromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(620)1-[3-cyano-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(621)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(622)1-[N-[[4-(1,3-Dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(623)1-[3-Methyl-N-[[4-[3,4-dihydro-2(1H)-oxothieno[3,4-d]-pyrimidin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(624)1-[N-[[4-[1,3-Dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(625)1-[N-[[4-[1,3-Dihydro-4-[(3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(626)1-[3-Bromo-N-[[4-[1,3-dihydro-4-[(3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(627)1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxothieno[3,4-d]-pyrimidin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(628)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(629)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperazine

(630)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine

(631)(R,S)-4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)-phenyl]methyl]-N-[2-(4-methyl-1-piperazinyl)ethyl]-butanamide

(632)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(1H-tetrazol-5-yl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(633)1-[3-Bromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine

(634)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(2-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(635)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[2-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(636)1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-nitro-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine

(637)(R,S)-1-[2-[(4-Amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(638)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[2-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(639)(R,S)-1-[2-[[3,5-Bis-(trifluoromethyl)phenyl]methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(640)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dimethoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(641)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(2-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(642)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dimethoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(643)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(4-piperidinyl)-piperidine

(644)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(645)(R,S)-1-[2-[(3-Bromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(646)(R,S)-1-[2-[(3-Bromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(647)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-propen-3-yl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(648)(R,S)-1-[2-[3-(Biphenylyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(649)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(pyridinyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(650)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(2-thiazolyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(651)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(2-furyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(652)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-propylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(653)(R,S)-1-[4-(2,4-Dihydro-5-phenyl-3(3H)-oxotriazol-2-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(654)(R,S)-1-[4-[1,3-Dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl]-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(655)(R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(656)(R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(657)1-[2-[(1,2,3,4-Tetrahydro-1-naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine(mixture of diastereomers)

(658)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(659)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(660)(R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(661)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(662)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(663)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(664)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine

(665)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(666)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(667)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine

(668)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine

(669)(R,S)-1-[2-[3,5-Dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine

(670)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(671)(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine

(672)(R,S)-1-[2-[(3,4-Dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-[4-(dimethylaminomethyl)phenyl]-piperidine

and the salts thereof.

The compounds of general formula I are prepared by methods which areknown in principle, particularly using processes derived from peptidechemistry (cf. for example Houben-Weyl, Methoden der Organischen Chemie,Vol. 15/2). The amino protecting groups used may be those described inHouben-Weyl, Methoden der Organischen Chemie, Vol. 15/1, of whichurethane protecting groups such as the fluorenylmethoxycarbonyl,phenylmethoxycarbonyl or tert.-butyloxycarbonyl group are preferred. Anyfunctional groups present in the groups R² and/or A of the compounds ofgeneral formula I or in the precursors thereof are additionallyprotected by suitable protecting groups in order to prevent sidereactions (cf. for example: G. B. Fields et al., Int. J. Peptide ProteinRes. 35, 161 (1990); T. W. Greene, Protective Groups in OrganicSynthesis). Examples of side-chain-protected amino acids of this kindinclude, in particular, Arg(NO₂), Arg(Mtr), Arg(di-Z), Arg(Pmc)Lys(Boc), Lys(Z), Orn(Boc), Orn(Z), Lys(Cl-Z) which are commerciallyobtainable, possibly in the form of derivatives. Particular care shouldbe taken to ensure that so-called orthogonal combinations of protectinggroups are used to protect the α-amino and the side chain amino group,e.g.:

Protection of the N (side chain) N^(α)-protection p-ToluenesulphonylPhenylmethoxycarbonyl tert.Butyloxycarbonyl Phenylmethoxycarbonyl(4-Methoxyphenyl)methoxycarbonyl tert. ButoxycarbonylAdamantyloxycarbonyl BiphenylylisopropyloxycarbonylIsonicotinoyloxycarbonyl o-Nitrophenylsulphenyl Formyl tert.Butoxycarbonyl Phenylmethoxycarbonyl p-Toluenesulphonylo-Nitrophenylsulphenyl Biphenylylisopropyloxycarbonyl9-Fluorenylmethoxycarbonyl Acetyl, Trifluoroacetyl,tert.Butyloxycarbonyl Formyl, (2-Chlorophenyl)- methoxycarbonyl,(4-Chloro- phenyl) methoxycarbonyl, 4-(Nitrophenyl)methoxycar- bonyl,Phthaloyl

Instead of protecting amino groups in the side chain, amino acids orderivatives thereof which carry precursor functions and in particularare substituted by nitro or cyano in the side chain, such as5-o-cyanonorvalin may also be used.

The basic functions in the side chains of α-amino acids which are notcommercially obtainable and which are characterised, for example, by(aminoiminomethyl) groups, may be protected in the same way as is usedfor protecting the side chains of arginine and its derivatives (cf. alsoM. Bodanszky, “Peptide Chemistry”, Springer-Verlag, 1988, p. 94-97);protecting groups which are particularly suitable for the(aminoiminomethyl)- group are the p-toluenesulphonyl, mesitylenesulphonyl—(Mts), methoxytrimethylphenylsulphonyl—(Mtr),2,2,5,7,8-pentamethylchroman-6-sulphonyl—(Pmc),pentachlorophenoxycarbonyl- and nitro-protecting groups.

For the actual coupling, the methods known from peptide chemistry areused (see Houben-Weyl, for example, Methoden der Organischen Chemie,Vol. 15/2). It is preferable to use carbodiimides such asdicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) orethyl-(3-dimethylaminopropyl)-carbodiimide,O-(1H-benzotriazol-1-yl)N,N-N′,N′-tetramethyluroniumhexafluorophosphate(HBTU) or tetrafluoroborate (TBTU) or1H-benzotriazol-1-yloxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP). By the addition of 1-hydroxybenzotriazole(HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt)racemisation may additionally be suppressed, if desired, or the reactionrate may be increased. The couplings are normally carried out withequimolar amounts of the coupling components and the coupling reagent insolvents such as dichloromethane, tetrahydrofuran, acetonitrile,dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone(NMP) or mixtures thereof and at temperatures between −30 and +30° C.,preferably between −20 and +20° C. If necessary,N-ethyl-diisopropylamine (DIEA) is preferred as an additional auxiliarybase (Hünig base).

The so-called “anhydride method” (cf. also M. Bodanszky, “PeptideChemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles ofPeptide Synthesis”, Springer-Verlag 1984, p. 21-27) was used as anothercoupling method for the synthesis of compounds of general formula I. The“mixed anhydride method” is preferred, in the variant according toVaughan (J. R. Vaughan Jr., J. Amer. Chem.Soc. 73, 3547 (1951)), inwhich the mixed anhydride is obtained from the optionally N²-protectedα-amino acid which is to be coupled, and the mono-isobutylcarbonate,using isobutylchlorocarbonate in the presence of base such as4-methylmorpholine or 4-ethylmorpholine. The preparation of this mixedanhydride and the coupling with amines are carried out in a one-potprocess using the above-mentioned solvents at temperatures between −20and +20° C., preferably between 0 and +20° C.

Any protecting groups present in the side chains of α-amino acid partialstructures are finally cleaved, after the formation of the N- andC-terminally substituted amino acid derivative, with suitable reagentswhich are also known from the literature in principle, specificallyarylsulphonyl and hetarylsulphonyl protecting groups, preferably byacidolysis, i.e. by the action of strong acids, preferablytrifluoroacetic acid, nitro- and arylmethoxycarbonyl protecting groupsare preferably cleaved by hydrogenolysis, e.g. using hydrogen in thepresence of palladium black and with glacial acetic acid as solvent. Ifthe substrate contains functions which are sensitive to hydrogenolysis,e.g. halogen atoms such as chlorine, bromine or iodine, a phenylmethanolor hetarylmethanol function or some other benzyl heteroatom bond,particularly a benzyl-oxygen bond, the nitro group may also be cleavednon-hydrogenolytically, e.g. with zinc/2N trifluoroacetic acid (cf. alsoA. Turan, A. Patthy and S. Bajusz, Acta Chim. Acad. Sci. Hung, Tom. 85(3), 327-332 [1975]; C.A. 83, 206526y [1975]), with tin(II)-chloride in60% aqueous formic acid (see also: SUNSTAR KK, JA-A-3271-299), with zincin the presence of acetic acid (cf. also: A. Malabarba, P. Ferrari, G.Cietto, R. Pallanza and M. Berti, J. Antibiot. 42 (12), 1800-1816(1989)) or excess aqueous 20% titanium(III)-chloride in aqueous methanoland in the presence of aqueous ammonium acetate buffer at 24° C. (seealso: R. M. Freidinger, R. Hirschmann and D. F. Veber, J. Org. Chem. 43(25), 4800-4803 [1978]).

Any precursor functions which may be present in the side chain of theα-amino acid may also subsequently be converted by hydrogenolysis intothe desired amino functions; nitroalkyl groups yield aminoalkyl groupsunder conditions which will be familiar to the chemist, whilst the cyanogroup is converted into the aminomethyl group.

Alternatively, nitrile functions may also be reduced with complexhydrides which are selective in relation to other critical functionscontained in the molecule, particularly amide groups (cf. also: J.Seyden-Penne, “Reductions by the Alumino- and Borohydrides in OrganicSynthesis”, VCH Publishers Inc., 1991, p. 132ff.), e.g. with sodiumborohydride in methanol and in the presence of cobalt(II)-chloride, withsodium borohydride in tetrahydrofuran in the presence of trifluoroaceticacid or with tetrakis-(n-butyl)-ammonium borohydride in dichloromethane;the reduction of aliphatic nitro function to the primary amino-functionis also possible with sodium borohydride in the presence oftin(II)-chloride or copper(II)-acetylacetonate, without affecting thecarboxamide groups present in type I compounds (see also: J.Seyden-Penne, ibid. p. 137ff.).

The following methods are particularly suitable for preparing thecompounds of general Formula I according to the invention:

a) In order to prepare compounds of general formula I, wherein

R denotes an unbranched C₁₋₇-alkyl group which may be substituted in theω-position

by a C₄₋₁₀-cycloalkyl group, by one or two phenyl groups, by a1-naphthyl, 2-naphthyl or biphenylyl group,

by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-2H-2-oxoimidazopyridinyl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-ylgroup, wherein the latter two groups may each be mono- or disubstitutedin the 4- and/or 5-position or in the 5- and/or 6-position by lowerstraight chained or branched alkyl groups, by phenyl, biphenylyl,pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl- or1-methylimidazolyl-groups and the substituents may be identical ordifferent,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or additional nitrogen atom,whilst a nitrogen atom of an imino group may be substituted by an alkylgroup,

or by a 6-membered heteroaromatic ring linked via a carbon atom, whichcontains one, two or three nitrogen atoms,

whilst a 1,4-butadienylene group may be attached both to theabove-mentioned 5-membered heteroaromatic monocyclic rings and to the6-membered heteroaromatic monocyclic rings, in each case via twoadjacent carbon atoms, and the bicyclic heteroaromatic rings thus formedmay also be bound via a carbon atom of the 1,4-butadienylene group, and

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkyl groups in the ω-position and optionallyalso partially hydrogenated mono- and bi-cyclic heteroaromatic rings inthe carbon skeleton may additionally be mono-, di- or trisubstituted byfluorine, chlorine or bromine atoms or by alkyl groups, C₃₋₈-cycloalkylgroups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl,alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl,benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl- ortrifluoromethylsulphonyl groups, wherein the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino andbenzoylmethylamino groups may in turn additionally be substituted in thephenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl,trifluoromethyl, amino or acetylamino group,

or the group of formula

 wherein

R⁵, R⁶, R⁷, R^(N), Y¹, o and p are as hereinbefore defined,

Y² denotes a CH— group and

Z denotes an NR¹— group, wherein R¹ is as hereinbefore defined:

coupling carboxylic acids of general formula VII,

RCO₂H  (VII)

wherein

R is as hereinbefore defined,

with compounds of general formula VIII,

 wherein

R², R³, R⁴, R¹¹, A, X, m and n are as hereinbefore defined, and

Z denotes an NR¹— group, wherein R¹ is as hereinbefore defined, and, ifnecessary, subsequently cleaving any protecting groups or modifyingprecursor functions in accordance with the methods describedhereinbefore.

The coupling is carried out using the methods known from peptidechemistry described above, particularly using DCC, DIC, HBTU, TBTU orBOP as reagents or using the mixed anhydride method.

b) In order to prepare compounds of general formula I wherein R isdefined as in a), Z denotes the NR¹— group and R¹, R², R³, R⁴, R¹¹, A,X, m and n are as hereinbefore defined:

coupling compounds of general formula IX,

R—CO—Nu  (IX)

wherein

R is defined as in a) and

Nu denotes a leaving group, for example a halogen atom such as thechlorine, bromine- or iodine atom, an alkylsulphonyloxy group having 1to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy ornaphthylsulphonyloxy group optionally mono-, di- or trisubstituted bychlorine or bromine atoms or by methyl- or nitro groups, wherein thesubstituents may be identical or different, a 1H-imidazol-1-yl, a1H-pyrazol-1-yl- optionally substituted by 1 or 2 methyl groups in thecarbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl,1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl,2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl,pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy,2(1H)-oxopyridin-1-yloxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy,1H-benzotriazol-1-yloxy or azide group,

with compounds of general formula VIII,

 wherein

R², R³, R⁴, R¹¹, A, X, m and n are as hereinbefore defined and

Z denotes an NR¹— group, whilst R¹ is as hereinbefore defined,

and, if necessary, subsequently cleaving protecting groups or modifyingprecursor functions using the methods described above.

The reaction is carried out under Schotten-Baumann- orEinhorn-conditions, i.e. the components are reacted in the presence ofat least one equivalent of an auxiliary base at temperatures between−50° C. and +120° C., preferably between −10° C. and +30° C., optionallyin the presence of solvents. Auxiliary bases which may be used arepreferably alkali- metal and alkaline earth metal hydroxides, e.g.sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metalcarbonates, e.g. sodium carbonate, potassium carbonate or cesiumcarbonate, alkali metal acetate, e.g. sodium- or potassium acetate, aswell as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine,quinoline, triethylamine, N-ethyl-diisopropylamine,N-ethyl-dicyclohexylamine, 1,4-Diazabicyclo[2,2,2]octane or1,8-diazabicyclo[5,4,0]undec-7-ene, whilst the solvents which may beused include, for example, dichloromethane, tetrahydrofuran,1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide,N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkalineearth metal hydroxides, alkali metal carbonates or -acetates are used asauxiliary bases, water may also be added to the reaction mixture as acosolvent.

c) In order to prepare compounds of general formula I wherein

R denotes an unbranched C₁₋₆-alkylamino group optionally substituted atthe nitrogen atom by a C₁₋₆-alkyl group or by a phenylmethyl group,which may be substituted in the ω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylylgroup,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or an additional nitrogenatom, whilst a nitrogen atom of an imino group may be substituted by analkyl group, or

by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene groupmay be attached both to the 5-membered and to the 6-memberedheteroaromatic monocyclic rings via two adjacent carbon atoms in eachcase and the bicyclic heteroaromatic rings thus formed may also be boundvia a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkyl moiety of the alkylamino groups in theω-position and optionally partially hydrogenated mono- and bicyclicheteroaromatic rings in the carbon skeleton may additionally be mono-,di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkylgroups, C₃₋₈-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl- ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino-and benzoylmethylamino groups in turn may additionally be substituted inthe phenyl moiety by a fluorine, chlorine or bromine atom or by analkyl, trifluoromethyl, amino- or acetylamino group,

or the group of formula

 wherein

R⁵, R⁶, R⁷, R^(N), Y¹, o and p are as hereinbefore defined,

Y² denotes the N-atom and

Z denotes the NR¹— group, wherein R¹ is as hereinbefore defined:

reacting amines of general formula X

R—H  (X)

wherein

R is as hereinbefore defined, with carbonic acid derivatives of generalXI

 X¹ is a nucleofugic group, preferably the 1H-imidazol-1-yl,1H-1,2,4-triazol-1-yl, trichloromethoxy- or 2,5-dioxopyrrolidin-1-yloxygroup,

and with compounds of general formula VIII,

 wherein

R², R³, R⁴, R¹¹, A, X, m and n are as hereinbefore defined and

Z denotes an NR¹— group, wherein R¹ is as hereinbefore defined,

and, if necessary, subsequently cleaving any protecting groups ormodifying any precursor functions using the method describedhereinbefore.

The theoretically two-step reactions are generally carried out asone-pot processes, preferably by reacting one of the two components X orVIII with equimolar amounts of the carbonic acid derivative of generalformula XI in a suitable solvent at fairly low temperature, in the firststep, and then adding at least equimolar amounts of the other componentVIII or X and finishing the reaction at elevated temperature. Thereactions with bis-(trichloromethyl)-carbonate are preferably carriedout in the presence of at least 2 equivalents (based onbis-(trichloromethyl)-carbonat) of a tertiary base, e.g. triethylamine,N-ethyl-diisopropylamine, pyridine, 1,5-diazabicyclo[4,3,0]non-5-ene,1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene.Examples of solvent, which should be anhydrous, include tetrahydrofuran,dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone,1,3-dimethyl-2-imidazolidinone or acetonitrile, ifbis-(trichloromethyl)-carbonate is used as the carbonyl component,anhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethaneor trichloroethylene are preferred. The reaction temperatures arebetween −30 and +25° C. for the first step of the reaction, preferablybetween −5 and +10° C., and between +15° C. and the boiling temperatureof the solvent used, preferably between +20° C. and +70° C. for thesecond step of the reaction (cf. also: H. A. Staab and W. Rohr,“Synthesen mit heterocyclischen Amiden (Azoliden)”, Neuere Methoden derPräparativen Organischen Chemie, Band V, p. 53-93, Verlag Chemie,Weinheim/Bergstr., 1967; P. Majer and R. S. Randad, J. Org. Chem. 59,1937-1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara und H.Ogura, Tetrahedron Letters 24 (42), 4569-4572 (1983)).

d) In order to prepare compounds of general formula I wherein thecarbonyl group linked to the groups R and Z denotes a urea carbonylgroup, in which the urea carbonyl is flanked by at least one NH— group,and wherein

R denotes an unbranched C₁₋₆-alkylamino group optionally additionallysubstituted at the nitrogen atom by a C₁₋₆-alkyl group or by aphenylmethyl group, which may be substituted in the ω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylylgroup,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or1,3-dihydro-2H-2-oxoimidazom[4,5-b]pyridin-3-yl-group,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or an additional nitrogenatom, whilst a nitrogen atom of an imino group may be substituted by analkyl group, or

by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene groupmay be attached both to the 5-membered and to the 6-memberedheteroaromatic monocyclic rings via two adjacent carbon atoms in eachcase and the bicyclic heteroaromatic rings thus formed may also be boundvia a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkyl moiety of the alkylamino groups in theω-position and optionally partially hydrogenated mono- and bicyclicheteroaromatic rings in the carbon skeleton may additionally be mono-,di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkylgroups, C₃₋₈-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl- ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino-and benzoylmethylamino groups in turn may additionally be substituted inthe phenyl moiety by a fluorine, chlorine or bromine atom or by analkyl, trifluoromethyl, amino or acetylamino group,

or the group of formula

 wherein

R⁵, R⁶, R⁷, R^(N), Y¹, o and p are as hereinbefore defined and

Y² denotes the N-atom,

Z denotes the group NR¹ and

R¹ denotes a hydrogen atom or, provided that, R denotes an unbranchedalkylamino group unsubstituted at the nitrogen atom and optionallysubstituted in the ω-position, R¹ may also denote an alkyl orphenylalkyl group:

Reacting amines of general formula X′,

R—H  (X′)

wherein R is as hereinbefore defined,

with carbonic acid derivatives of general formula XI′,

 wherein

X² denotes a phenoxy group, if X³ is the (1H)-1,2,3,4-tetrazol-1-ylgroup, the 4-nitrophenoxy group, if X³ is the 4-nitrophenoxy group, andthe chlorine atom if X³ is the 2,4,5-trichlorophenoxy group, and withcompounds of general formula VIII′,

 wherein

R², R³, R⁴, R¹¹, X, A, m and n are as hereinbefore defined and

R¹ denotes a hydrogen atom or, provided that R is an unbranchedalkylamino group unsubstituted at the nitrogen and optionallysubstituted in the ω-position, R¹ may also denote an alkyl orphenylalkyl group, and

if necessary, subsequently cleaving protecting groups or modifyingprecursor functions using the methods described hereinbefore.

The reactions are in two steps, in principle, with intermediateformation of urethanes, which can be isolated. However, the reactionsmay also be carried out as one-pot reactions. Preferably, in the firststep, one of the two components X′ or VIII′ is reacted with equimolaramounts of the carbonic acid derivative of general formula XI′ in asuitable solvent at low temperature, then at least equimolar amounts ofthe other component VIII′ or X′ are added and the reaction is completedat elevated temperature. The reactions are preferably carried out inanhydrous solvents, e.g. in tetrahydrofuran, dioxane, dimethylformamide,dimethylacetamide, N-methyl-2-pyrrolidone,1,3-dimethyl-2-imidazolidinone, acetonitrile or anhydrouschlorohydrocarbons e.g. dichloromethane, 1,2-dichloroethane ortrichloroethylene. The reaction temperatures are between −15 and +40°C., preferably between −10 and +25° C. for the first step, between +20°C. and the boiling temperature of the solvent used, preferably between+20° C. and 100° C. for the second reaction step (cf. also: R. W.Adamiak and J. Stawinski, Tetrahedron Letters 1977, 22, 1935-1936; A. W.Lipkowski, S. W. Tam and P. S. Portoghese, J. Med. Chem. 29, 1222-1225(1986); J. Izdebski and D. Pawlak, Synthesis 1989, 423-425).

e) In order to prepare compounds of general formula I wherein Z denotesthe group NH and

R denotes an unbranched C₁₋₆-alkylamino group optionally substituted atthe nitrogen atom by a C₁₋₆-alkyl group or by a phenylmethyl group,which may be substituted in the ω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylylgroup,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or an additional nitrogenatom, whilst a nitrogen atom of an imino group may be substituted by analkyl group, or

by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene groupmay be attached both to the 5-membered and to the 6-memberedheteroaromatic monocyclic rings via two adjacent carbon atoms in eachcase and the bicyclic heteroaromatic rings thus formed may also be boundvia a carbon atom of the 1,4-butadienylene group, whilst the phenyl,naphthyl and biphenylyl groups mentioned above for the substitution ofthe alkyl groups in the ω-position and optionally partially hydrogenatedmono- and bicyclic heteroaromatic rings in the carbon skeleton mayadditionally be mono-, di- or trisubstituted by fluorine, chlorine orbromine atoms, by alkyl groups, C₃₋₈-cycloalkyl groups, nitro, alkoxy,phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl,alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy,amino, acetylamino, propionylamino, benzoyl, benzoylamino,benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino-and benzoylmethylamino groups in turn may additionally be substituted inthe phenyl moiety by a fluorine, chlorine or bromine atom or by analkyl, trifluoromethyl, amino or acetylamino group,

or the group of formula

 wherein

R⁵, R⁶, R⁷, R^(N), Y¹, o and p are as hereinbefore defined and Y²denotes an N-atom:

Reacting isocyanates of general formula XII,

 wherein

R², R³, R⁴, R¹¹, A, X, m and n are as hereinbefore defined,

with amines of general formula X,

R—H  (X)

wherein

R is as hereinbefore defined and, if necessary, subsequently cleavingprotecting groups or modifying precursor functions using the processesdescribed above.

The reaction is carried out at temperatures between 0° C. and 150° C.,preferably between 20° C. and 100° C., optionally in the presence ofanhydrous solvents, e.g. tetrahydrofuran, 1,4-dioxane,dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or1,3-dimethyl-2-imidazolidinone or mixtures thereof.

f) In order to prepare compounds of general formula I wherein

R denotes an unbranched C₁₋₆-alkylamino group unsubstituted at thenitrogen atom, which may be substituted in the ω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylylgroup,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or an additional nitrogenatom, whilst a nitrogen atom of an imino group may be substituted by analkyl group, or

by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene groupmay be attached both to the 5-membered and to the 6-memberedheteroaromatic monocyclic rings via two adjacent carbon atoms in eachcase and the bicyclic heteroaromatic rings thus formed may also be boundvia a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkylamino groups in the ω-position andoptionally partially hydrogenated mono- and bicyclic heteroaromaticrings in the carbon skeleton may additionally be mono-, di- ortrisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups,C₃₋₈-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl- ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino-and benzoylmethylamino groups in turn may additionally be substituted inthe phenyl moiety by a fluorine, chlorine or bromine atom or by analkyl, trifluoromethyl, amino- or acetylamino group, and

Z denotes the NR¹— group wherein R¹ is as hereinbefore defined:

Reacting isocyanates of general formula XIII,

 R═C═O  (XIII)

wherein R is as hereinbefore defined, with compounds of general formulaVIII,

wherein R², R³, R⁴, R¹, A, X, m and n are as hereinbefore defined and

Z denotes an NR¹— group, wherein R¹ is as hereinbefore defined,

and, if necessary, subsequently cleaving any protecting groups ormodifying the precursor functions using the methods describedhereinbefore.

The reaction is carried out at temperatures between 0 and 150° C.,preferably at temperatures between 20 and 100° C., and optionally in thepresence of anhydrous solvents, e.g. tetrahydrofuran, 1,4-dioxane,dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or1,3-dimethyl-2-imidazolidinone.

g) In order to prepare compounds of general formula I wherein R, Z, R²,R³, R⁴, R¹¹, A, m and n have the meanings given hereinbefore and X is ashereinbefore defined, provided that A does not denote a bond or Xdenotes an oxygen atom, if A denotes a single bond:

Coupling carboxylic acids of general formula XIV,

 wherein

R, Z, R¹¹, m and n are as hereinbefore defined,

R²′ has the meanings given for R² hereinbefore or denotes a group R²substituted by the above-mentioned protecting groups,

A′ has the meanings given for A hereinbefore or, if A denotes thedivalent group of an amino acid, it optionally bears in the side chain aprecursor group for the group R⁹, e.g. a cyanopropyl group,

to compounds of general formula XV,

H—NR³R⁴  (XV)

 wherein

R³ and R⁴ are as hereinbefore defined,

and if necessary subsequent cleaving of protective groups ormodification of precursor functions using the methods described above.

The coupling is carried out using the methods known from peptidechemistry and described hereinbefore, particularly using DCC, DIC, HBTU,TBTU or BOP as reagents or using the mixed anhydride method.

If the starting compound XIV used is enantiomerically pure, partialracemisation of the C-terminal amino acid must be expected during thecoupling step and possibly quantitative racemisation must be expected iftriethylamine is used as the auxiliary base and dimethylformamide,dimethylacetamide or N-methyl-pyrrolidone is used as solvent.

h) In order to prepare compounds of general formula I wherein X denotesthe oxygen atom:

Coupling carboxylic acids of general formula XVI,

 wherein

R, Z, R¹¹, m and n are as hereinbefore defined and

R²′ has the meanings given for R² hereinbefore or denotes a group R²substituted by the above-mentioned protecting groups,

to compounds of general formula XVII,

 wherein

A′ has the meanings given for A hereinbefore or, if A denotes thedivalent group of an amino acid, A′ optionally bears in the side chain aprecursor group for the group R⁹, e.g. a cyanopropyl group, and

R³ and R⁴ are as hereinbefore defined,

and if necessary subsequently cleaving protecting groups or modifyingprecursor functions using the methods described above.

The coupling is carried out using the methods known from peptidechemistry and described above, particularly using DCC, DIC, HBTU, TBTUor BOP as reagents or using the mixed anhydride method.

If the starting compound XVI used is enantiomerically pure, during thecoupling step partial racemisation must be expected or, if triethylamineis used as the auxiliary base and dimethylformamide, dimethylacetamideor N-methyl-pyrrolidone is used as solvent, quantitative racemisationmust be expected based on the chiral centre of XVI.

i) In order to prepare compounds of general formula I wherein

R denotes an unbranched C₁₋₆-alkylamino group optionally substituted atthe nitrogen atom by a C₁₋₆-alkyl group or by a phenylmethyl group,which may be substituted in the ω-position

by a C₄₋₁₀-cycloalkyl group,

by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylylgroup,

by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl,2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl,2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl,3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-1-yl,3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl,2(1H)-oxoquinoxalin-3-yl,1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl,1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl,3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl,3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,

by a 5-membered heteroaromatic ring linked via a carbon atom, whichcontains a nitrogen, oxygen or sulphur atom or, in addition to anitrogen atom, contains an oxygen, sulphur or an additional nitrogenatom, whilst a nitrogen atom of an imino group may be substituted by analkyl group, or

by a 6-membered heteroaromatic ring linked via a carbon atom andcontaining 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene groupmay be attached both to the 5-membered and to the 6-memberedheteroaromatic monocyclic rings via two adjacent carbon atoms in eachcase and the bicyclic heteroaromatic rings thus formed may also be boundvia a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above forthe substitution of the alkyl moiety of the alkylamino groups in theω-position and optionally partially hydrogenated mono- and bicyclicheteroaromatic rings in the carbon skeleton may additionally be mono-,di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkylgroups, C₃₋₈-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy,trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino,propionylamino, benzoyl, benzoylamino, benzoylmethylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,(hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,(4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphinyl ortrifluoromethylsulphonyl groups, whilst the substituents may beidentical or different and the above-mentioned benzoyl, benzoylamino andbenzoylmethylamino groups in turn may additionally be substituted in thephenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl,trifluoromethyl, amino or acetylamino group,

or the group of formula

 wherein

R⁵, R⁶, R⁷, R^(N), Y¹, o and p are as hereinbefore defined and

Y² denotes an N-atom,

Z represents the methylene group,

X denotes two hydrogen atoms,

A denotes a single bond,

m denotes the value 1 and

n denotes the value 0:

Coupling carboxylic acids of general formula XVIII,

 wherein

R², R³ and R⁴ are as hereinbefore defined,

with amines of general formula X,

R—H  (X)

wherein R is as hereinbefore defined.

The coupling is carried out using the methods known from peptidechemistry and described above, particularly using DCC, DIC, HBTU, TBTUor BOP as reagents or using the mixed anhydride method.

j) In order to prepare compounds of general formula I wherein R³ and R⁴have the meanings given hereinbefore with the exception of the hydrogenatoms, Z denotes a methylene group, X denotes two hydrogen atoms, Adenotes a single bond, m is the number 1 and n is the number 0:

Reacting secondary amines of general formula XVa,

H—NR³′R⁴′  (XVa)

 wherein

R³′ and R⁴′ have the meanings given for R³ and R⁴ hereinbefore with theexception of hydrogen atoms,

with formaldehyde and CH-acid compounds of general formula XIX,

wherein

R is as hereinbefore defined and

 R² is as hereinbefore defined, but with the proviso that any acidfunctions present such as hydroxy groups are appropriately protected bysuitable protecting groups.

The reaction is preferably carried out in a slightly acidic medium,using alcohols, e.g. methanol or ethanol, or lower aliphatic carboxylicacids, such as glacial acetic acid, as solvents and at temperaturesbetween room temperature and the boiling point of the solvent inquestion. In a preferred variant, an inorganic acid salt such as thehydrochloride of a secondary amine of general formula XVa is heated withparaformaldehyde and a ketone of general formula XIX in glacial aceticacid to temperatures between 50° C. and 80° C.

k) In order to prepare compounds of general formula I wherein

R, R², R³, R⁴, R¹¹, X, Z, m and n are as hereinbefore defined and

A denotes the divalent group of formula III

(linked to the NR³R⁴— group via the —CX—0 group)

 wherein

R⁸ denotes the hydrogen atom or an alkyl or phenylalkyl group and

R⁹ denotes an unbranched C₁₋₅-alkyl group substituted in the ω-positionby an aminoiminomethylamino group:

Reacting compounds of general formula XX,

 wherein

R, R², R³, R⁴, R¹¹, X, Z, m and n are as hereinbefore defined,

R⁸ denotes a hydrogen atom or an alkyl or phenylalkyl group and

R⁹ denotes an unbranched C₁₋₅-alkyl group substituted in the ω-positionby a primary amino group,

with carbonic acid derivatives of general formula XXI,

 wherein

Nu² is a leaving group, e.g. an alkoxy, alkylthio, alkylsulphinyl oralkylsulphonyl group each having 1 to 10 carbon atoms in alkyl moiety,e.g. a methoxy, ethoxy, methylthio, ethylthio, methylsulphinyl,ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, methylsulphonyl orethylsulphonyl group, the chlorine atom, the SO₂H, SO₃H— or OPOCl₂—group, or the group of general formula XXII,

 wherein

R¹⁵ and R¹⁶, which may be identical or different, denote hydrogen atomsor C₁₋₃-alkyl groups.

Occasionally, for example when Nu² is an alkoxy group, instead of usingthe compounds of general formula XXI it is advantageous to use theinorganic acid salts thereof, e.g. the neutral sulphates orhydrochlorides thereof.

The reactions are carried out analogously to methods known from theliterature (see G. B. L. Smith, J. Amer. Chem. Soc. 51, 476 [1929]; B.Rathke, Chem. Ber. 17, 297 [1884]; R. Phillips and H. T. Clarke, J.Amer. Chem. Soc. 45, 1755 [1923]; S. J. Angyal and W. K. Warburton, J.Amer. Chem. Soc. 73, 2492 [1951]; H. Lecher and F. Graf, Chem. Ber. 56,1326 [1923]; J. Wityak, S. J. Gould, S. J. Hein and D. A. Keszler, J.Org. Chem. 52, 2179 [1987]; T. Teraji, Y. Nakai, G. J. Durant,WO-A-81/00109, Chem. Abstr. 94, 192336z [1981]; C. A. Maryanoff, R. C.Stanzione, J. N. Plampin and J. E. Mills, J. Org. Chem. 51, 1882-1884[1986]; A. E. Miller and J. J. Bischoff, Synthesis 1986, 777; R. A. B.Bannard, A. A. Casselman, W. F. Cockburn and G. M. Brown, Can. J. Chem.36, 1541 [1958]; Aktieselskabet Grea, Kopenhagen, DE 28 26 452-C2; K.Kim. Y-T. Lin and H. S. Mosher, Tetrah. Letters, 29, 3183-3186 [1988];H. B. Arzeno et al., Synth. Commun. 20, 3433-3437 [1990]; H. Bredereckand K. Bredereck, Chem. Ber. 94, 2278 [1961]; H. Eilingsfeld, G.Neubauer, M. Seefelder and H. Weidinger, Chem. Ber. 97, 1232 [1964]; P.Pruszynski, Can. J. Chem. 65, 626 [1987]; D. F. Gavin, W. J. Schnabel,E. Kober and M. A. Robinson, J. Org. Chem. 32, 2511 [1967]; N. K. Hart,S. R. Johns, J. A. Lamberton and R. I. Willing, Aust. J. Chem. 23, 1679[1970]; CIBA Ltd., Belgisches Patent 655 403; Chem. Abstr. 64, 17481[1966]; R. A. B. Bannard, A. A. Casselman, W. F. Cockburn and G. M.Brown, Can. J. Chem. 36, 1541 [1958]; J. P. Greenstein, J. Org. Chem. 2,480 [1937]; F. L. Scott and J. Reilly, J. Amer. Chem. Soc. 74, 4562[1952]; W. R. Roush and A. E. Walts, J. Amer. Chem. Soc. 106, 721[1984], M. S. Bernatowicz, Y. Wu and G. R. Matsueda, J. Org. Chem. 57,2497-2502 [1992]; H. Tsunematsu, T. Imamura and S. Makisumi, J. Biochem.94, 123-128 [1983]) at temperatures between 0° C. and +100° C.,preferably between +40° C. and +80° C., using inert solvents, e.g.dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile,dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixturesthereof and, depending on the nature of the Nu²— group, frequently inthe presence of auxiliary bases, especially alkali metal carbonates suchas sodium- or potassium carbonate, or tertiary amines, preferablyN-ethyl-diisopropylamine or triethylamine.

The amino acids of general formula I modified according to the inventioncontain at least one chiral centre. If the group A is also chiral, thecompounds may occur in the form of two diastereomeric pairs ofantipodes. The invention includes the individual isomers as well as themixtures thereof.

The diastereomers are separated on the basis of their differentphysicochemical properties, e.g. by fractional crystallisation fromsuitable solvents, by high pressure liquid or column chromatographyusing chiral or preferably achiral stationary phases.

Racemates covered by general formula I may be separated, for example, byHPLC on suitable chiral stationary phases (e.g. Chiral AGP, ChiralpakAD). Racemates which contain a basic or acidic function can also beseparated by means of the diastereomeric optically active salts whichare formed on reacting with an optically active acid, e.g. (+)- or(−)-tartaric acid, (+)- or (−)-diacetyl tartaric acid, (+)- or(−)-monomethyltartrate or (+)-camphor sulphonic acid or an opticallyactive base such as (R)-(+)-1-phenylethylamine,(S)-(−)-1-phenylethylamine or (S)-brucine.

According to a conventional process for separating isomers, the racemateof a compound of general formula I is reacted with one of theabove-mentioned optically active acids or bases in equimolar amounts ina solvent and the crystalline, diastereomeric, optically active saltsobtained are separated on the basis of their different solubilities.This reaction may be carried out in solvents of any kind provided thatthey are sufficiently different in terms of the solubility of the salts.Preferably, methanol, ethanol or mixtures thereof are used, e.g. in aratio by volume of 50:50. Then each of the optically active salts isdissolved in water, neutralised with a base such as sodium carbonate orpotassium carbonate, sodium hydroxide solution or potassium hydroxidesolution, and in this way the corresponding free compound is obtained inthe (+)- or (−)-form.

The (R)-enantiomer alone or a mixture of two optically activediastereomeric compounds coming within the scope of general formula Imay also be obtained by carrying out the syntheses described above witha suitable reaction component in the (R)-configuration.

The starting materials of general formulae VII, IX, X, X′, XI, XII,XIII, XV, XVa, XVII, XXI, XXII required to synthesis the compounds ofgeneral formula I as well as the amino acids used are commerciallyavailable or may be prepared by methods known from the literature.

Compounds of general formula VIII wherein Z denotes the group NR¹ andthose of general formula VIII′ wherein X denotes the oxygen atom may beobtained from commonly available starting materials using methodsfamiliar to peptide chemists.

Isocyanates of general formula XII can easily be obtained from α-aminoacid derivatives of general formula VIII′ wherein R¹ denotes a hydrogenatom and the other groups are as hereinbefore defined, or from thehydrochlorides thereof by reacting with phosgene, diphosgene ortriphosgene in the presence of pyridine (see also: J. S. Nowick, N. A.Powell, T. M. Nguyen and G. Noronha, J. Org. Chem. 57, 7364-7366[1992]).

Carboxylic acids of general formulae XIV and XVI may be obtained fromthe corresponding carboxylic acid esters by saponification, preferablyin the presence of lithium hydroxide.

The carboxylic acids of general formula XVIII are obtained bysaponifying corresponding carboxylic acid esters which are in turnprepared from suitable secondary amines, 4-aryl-4-oxobutanoic acidesters and formaldehyde by Mannich reaction.

Compounds of general formula XIX may be obtained from suitable4-oxobutanoic acids and amines of general formula X using conventionalmethods.

The intermediate compounds of general formula XX come under generalformula I and are thus within the scope of the present application.These compounds may be obtained, for example, using processes a) to h)described herein.

The compounds of general formula I may be converted into theirphysiologically acceptable salts with inorganic or organic acids,particularly for pharmaceutical applications. Examples of suitable acidsfor this purpose include hydrochloric acid, hydrobromic acid, phosphoricacid, nitric acid, sulphuric acid, methanesulphonic acid,p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid,lactic acid, mandelic acid, malic acid, citric acid, tartaric acid ormaleic acid.

Moreover, if the new compounds of formula I thus obtained contain anacid function, for example a carboxy group, they may if desired beconverted into the addition salts thereof with inorganic or organicbases, more particularly for pharmaceutical use, into thephysiologically acceptable addition salts thereof. Bases which may beconsidered include, for example, sodium hydroxide, potassium hydroxide,ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine,diethanolamine and triethanolamine.

The new compounds of general formula I and the physiologicallyacceptable salts thereof have CGRP-antagonistic properties and exhibitgood affinities in CGRP-receptor binding studies. The compounds exhibitCGRP-antagonistic properties in the pharmacological test systemsdescribed hereinafter.

The following experiments were carried out to demonstrate the affinityof compounds of general formula I for human CGRP-receptors and theirantagonistic properties:

A. Binding studies with SK-N-MC-cells expressing human CGRP-receptor

SK-N-MC-cells are cultivated in Dulbecco's modified Eagle Medium. Themedium of confluent cultures is removed. The cells are washed twice withPBS-buffer (Gibco 041-04190 M), detached by the addition of PBS-buffermixed with 0.02% EDTA and isolated by centrifuging. After resuspensionin 20 ml of Balanced Salts Solution [BSS (in mM): NaCl 120, KCl 5.4,NaHCO₃ 16.2, MgSO₄ 0.8, NaHPO₄ 1.0, CaCl₂ 1.8, D-Glucose 5.5, HEPES 30,pH7.40] the cells are centrifuged twice at 100×g and resuspended in BSS.After the cell number has been determined the cells are homogenisedusing an Ultra-Turrax and centrifuged for 10 minutes at 3000×g. Thesupernatent is discarded and the pellet is recentrifuged and resuspended(1 ml/1000000 cells) in Tris-buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl₂,1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1%bacitracin. The homogenate is frozen at −80° C. The membranepreparations are stable for more than 6 weeks under these conditions.

After thawing, the homogenate is diluted 1:10 with assay buffer (50 mMTris, 150 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, pH 7.40) and homogenised for30 seconds with an Ultra-Turrax. 230 μl of the homogenate are incubatedat ambient temperature for 180 minutes with 50 pM of¹²⁵I-Iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) andincreasing concentrations of the test substances in a total volume of250 μl. Incubation is ended by rapid filtration using GF/B-glass fibrefilters treated with polyethyleneimine (0.1%) by means of a cellharvester. The protein-bound radioactivity is measured using agammacounter. The non-specific binding is defined as the radioactivitybound after the presence of 1 μM of human CGRP-alpha during incubation.

The concentration binding curves are analysed using a computer-aidednon-linear curve adaptation.

The compounds of general formula I show IC₅₀ values≦10000 nM in the testdescribed.

B. CGRP-Antagonism in SK-N-MC-cells

SK-N-MC-cells (1 million cells) are washed twice with 250 μl ofincubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1%BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After theaddition of CGRP (10 μl) as agonist in increasing concentrations (10⁻¹¹to 10⁻⁶ M) or additionally of substance in 3 to 4 differentconcentrations, incubation is continued for a further 15 minutes.

Intracellular cAMP is then extracted by the addition of 20 μl of 1M HCland centrifugation (2000×g, 4° C. for 15 minutes). The supernatants arefrozen in liquid nitrogen and stored at −20° C.

The cAMP contents of the samples are determined by radioimmunoassay(Amersham) and the pA₂-values of antagonistically acting substances aredetermined graphically.

The compounds of general formula I display CGRP-antagonistic propertiesin a dosage range between 10⁻¹¹ and 10⁻⁵ M in the in vitro test modeldescribed.

In view of their pharmacological properties the compounds of generalformula I and the salts thereof with physiologically acceptable acids orbases are thus suitable for acute and prophylactic treatment ofheadache, particularly migraine and cluster headaches. Moreover, thecompounds of general formula I also have a beneficial effect on thefollowing diseases: non-insulin-dependent diabetes mellitis (NIDDM),cardiovascular diseases, skin diseases, particularly thermal andradiation-induced skin damage including sunburn, inflammatory diseases,e.g. inflammatory joint diseases (arthritis), inflammatory lungdiseases, allergic rhinitis, asthma, diseases which involve excessivevasodilation and resultant reductions in circulation, e.g. shock andsepsis, as well as morphine tolerance. In addition, the compounds ofgeneral formula I have the effect of alleviating pain in general.

The dosage needed to achieve such effects is appropriately 0.0001 to 3mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, byintravenous or subcutaneous route, and 0.01 to 10 mg/kg of body weight,preferably 0.1 to 10 mg/kg of body weight, when administered orally,nasally or by inhalation, in each case 1 to 3 times a day.

For this purpose, the compounds of general formula I prepared accordingto the invention may be formulated, optionally in combination with otheractive substances, such as antiemetics, prokinetics, neuroleptics,antidepressants, neurokinin-antagonists, anti-convulsants,histamine-H1-receptor antagonists, antimuscarinics, β-blockers,α-agonists and α-antagonists, ergot alkaloids, mild analgesics,non-steroidal antiphlogistics, corticosteroids, calcium-antagonists,5-HT_(1D)-agonists or other antimigraine agents, together with one ormore inert conventional carriers and/or diluents, e.g. corn starch,lactose, glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethyleneglycol,propyleneglycol, cetylstearylalcohol, carboxymethylcellulose or fattysubstances such as hard fat or suitable mixtures thereof, to produceconventional galenic preparations such as plain or coated tablets,capsules, powders, suspensions, solutions, metering aerosol orsuppositories.

Thus, additional active substances which may be considered for theabove-mentioned combinations include, for example, meloxicam,ergotamine, dihydroergotamine, metoclopramide, domperidon,diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone,flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol,atenolol, clonidine, indoramine, carbamazepine, phenytoin, valproate,amitryptilin, lidocaine, diltiazem or sumatriptan and other5-HT_(1D)-agonists such as naratriptan, zolmitriptan, avitriptan,rizatriptan and eletriptan. The dosage for these active substances isappropriately 1/5 of the lowest dose normally recommended up to 1/1 ofthe normally recommended dosage, i.e. 20 to 100 mg of sumatriptan, forexample.

The invention further relates to the use of the compounds of generalformula I as valuable auxiliary agents for the production andpurification (by affinity chromatography) of antibodies and, aftersuitable radiolabelling, e.g. by direct labelling with ¹²⁵I or ¹³¹I orby tritiation of suitable precursors for example by replacing halogenatoms with tritium, in RIA- and ELISA assays and as diagnostic oranalytical aids in neurotransmitter research.

The Examples which follow are intended to illustrate the invention:

Preliminary Remarks

There are satisfactory elementary analyses, IR, UV, ¹H-NMR and generallymass spectra as well, for all the compounds. Unless otherwise specified,Rf values were determined using TLC ready-made plates of silica gel 60F₂₅₄ (E. Merck, Darmstadt, Product No. 5729) without chamber saturation.If there are no details of configuration, it is undecided whether thisis the pure enantiomer or whether partial or total racemisation hasoccurred. The following eluants or eluant mixtures were used forchromatography:

FM1=dichloromethane/cyclohexane/methanol/ammonia 7/1.5/1.5/0.2 (v/v/v/v)

FM2=dichloromethane/methanol/ammonia 7.5/2.5/0.5 (v/v/v)

FM3=dichloromethane/methanol 8/2 (v/v)

FM4=dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueousammonia=59/25/7,5/7,5/1 (v/v/v/v/v)

FM5=ethyl acetate/dichloromethane=7/3 (v/v)

FM6=ethyl acetate/petroleum ether=1/1 (v/v)

FM7=dichloromethane/methanol/conc. aqueous ammonia=80/20/1 (v/v/v)

The following abbreviations were used in the descriptions of theexperiments:

Mp.: melting point

(D): (decomposition)

DIEA: N,N-diisopropyl-ethylamine

Boc: (1,1-dimethylethoxy)carbonyl

TBTU:2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate

HOBt: 1-hydroxybenzotriazole-hydrate

CDT: 1,1′-carbonyldi(1,2,4-triazole)

THF: tetrahydrofuran

DMF: dimethylformamide

Fmoc: (9-fluorenylmethoxy)carbonyl

EE: ethyl acetate

PE: petroleum ether

LM: solvent

Lfd. No.: item number

The meanings of the symbols made up of letters and numbers used in theExamples are given in the following summary:

A. PREPARATION OF INTERMEDIATE COMPOUNDS EXAMPLE A1

Preparation of compounds of the general structure:

1,3-dihydro-4-(3-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one

a)4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-pipieridine

To a mixture of 20.0 g (0.10 mol) of4-amino-1-(1,1-dimethyl-ethoxycarbonyl)piperidine, 8.2 g (0.1 mol) ofanhydrous sodium acetate and 150 ml of dichloromethane was addeddropwise, with stirring and whilst maintaining a reaction temperature offrom 0° C. to +10° C., a solution of 25.0 g (0.109 mol) of3-methoxy-phenacylbromide in 50 ml of dichloromethane was addeddropwise. The mixture was stirred for 5 hours at room temperature, then19.5 g (0.296 mol) of sodium cyanate, 18 ml of glacial acetic acid and10 ml of water were added and stirring was continued for 12 hours atroom temperature. The mixture was stirred into 1 l of ice water, thedichloromethane phase was separated off, washed twice with 200 ml ofwater, 5% aqueous sodium hydrogen carbonate solution, 20% aqueous citricacid solution and once more with water, dried over magnesium sulphateand evaporated down in vacuo. The residue was taken up in methanol. Itwas left to stand overnight, the precipitate which crystallised out wassuction filtered, washed thoroughly with tert. butyl-methylether andafter drying in vacuo 11.5 g (30.8% of theory) of colourless crystalswere obtained.

MS: M⁺=373

The following were obtained accordingly:

(1)4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

R_(f): 0.51 (FM4)

(2)4-[1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

yield: 23.8% of theory

(3)4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

IR(KBr): 1685.7 cm⁻¹ (C═O)

(4)4-[1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-(1,-dimethylethoxycarbonyl)-piperidine

R_(f): 0.23 (dichloromethane/methanol 9/1 v/v)

IR(KBr): 1687.6 cm⁻¹ (C═O)

MS: M⁺=357

(5)4-[1,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

yield: 29.1% of theory

MS: M⁺=388

(6)4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

yield: 13.1% of theory

IR(KBr): 1685 cm⁻¹ (C═O)

MS: M⁺=421/423 (Br)

(7)4-[1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

IR(KBr): 1680, 1699 cm⁻¹ (C═O)

MS: M⁺=419

(8)4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

IR(KBr): 1682 cm⁻¹ (C═O)

MS: M⁺=388

(9)4-[4-(4-biphenylyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

yield: 21.6% of theory, colourless crystals

R_(f): 0.6 (ethyl acetate)

IR(KBr): 1681.8 cm⁻¹ (C═O)

(10)4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

yield: 30% of theory, crystals

IR(KBr): 1679.9 cm⁻¹ (C═O)

(11)4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

R_(f): 0.86 (FM1)

(12)4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

yield: 62% of theory, colourless crystals

R_(f): 0.34 (ethyl acetate)

IR(KBr): 1687 cm⁻¹ (C═O)

(13)4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

yield: 21% of theory

R_(f): 0.6 (ethyl acetate/methanol 9/1 v/v)

(14)4-[1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

Yield: 60% of theory

IR(KBr): 1682 cm⁻¹ (C═O)

MS: M⁺=359

(15)4-[4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

Yield: 3.2% of theory

IR(KBr): 1687.6 cm⁻¹ (C═O)

R_(f): 0.95 (dichloromethane/methanol 9/1 v/v)

(16)4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine

Yield: 4.6% of theory

IR(KBr): 1684 cm⁻¹ (C═O)

R_(f): 0.48 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV₂₅₄ ready-made filmsfor TLC)

b) 1,3-dihydro-4-(3-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one

The solution of 11.5 g (0.0308 mol) of4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidinein 150 ml of dichloromethane was mixed with 15 ml of trifluoroaceticacid and then stirred overnight at room temperature. The reactionmixture was evaporated down in vacuo, the residue was taken up in 10 mlof water and made distinctly ammoniacal. The resulting precipitate wassuction filtered, washed thoroughly with water and dried overnight at50° C. in vacuo. 7.0 g (83.1% of theory) of colourless crystals wereobtained, R_(f) value 0.2 (dichloromethane/methanol 9/1 v/v).

The following were obtained accordingly:

(1) 1,3-dihydro-4-phenyl-1-(4-piperidinyl)-2H-imidazol-2-one,

R_(f): 0.22 (FM1; Macherey-Nagel POLYGRAM® SIL G/UV₂₅₄ ready-made filmsfor TLC)

IR(KBr): 1672 cm⁻¹ (C═O)

(2) 1,3-dihydro-4-(4-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one

IR(KBr): 1670 cm⁻¹ (C═O)

MS: M⁺=273

(3)1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-1-(4-piperidinyl)-2H-imidazol-2-one

IR(KBr): 1687.6 cm⁻¹ (C═O)

(4) 1,3-dihydro-5-methyl-4-phenyl-1-(4-piperidinyl)-2H-imidazol-2-one

yield: 76.2% of theory

IR(KBr): 1679.9 cm⁻¹ (C═O)

MS: M⁺=257

(5) 1,3-dihydro-4-(3-nitrophenyl)-1-(4-piperidinyl)-2H-imidazol-2-one

yield: 94% of theory

IR(KBr): 1677.8 (C═O); 1137.8, 1197.6, 1349.9 (NO₂) cm⁻¹

(6) 4-(3-bromophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one

yield: quantitative

IR(KBr): 1676 cm⁻¹ (C═O)

(7) 1,3-dihydro-4,5-diphenyl-1-(4-piperidinyl)-2H-imidazol-2-one

IR(KBr): 1670 cm⁻¹ (C═O)

MS: M⁺=319

(8) 1,3-dihydro-4-(4-fluorophenyl)-1-(4-piperidinyl)-2H-imidazol-2-one

yield: 30% of theory

R_(f): 0.2 (eluant: ethyl acetate/methanol/conc. ammonia 9/1/0.3 v/v/v)

IR(KBr): 1682 cm⁻¹ (C═O)

(9) 4-(4-biphenylyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one

yield: quantitative

IR(KBr) of the trifluoroacetate: 1679.9 cm⁻¹ (C═O)

(10) 1,3-dihydro-4-(2-naphthyl)-1-(4-piperidinyl)-2H-imidazol-2-one

yield: 28.2% of theory

R_(f): 0.03 (FM1)

IR(KBr) of the trifluoroacetate: 1678 cm⁻¹ (C═O)

(11) 7-(2-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one

yield: 18.8% of theory

R_(f): 0.22 (FM1)

IR(KBr) of the trifluoroacetate: 1681.6 cm⁻¹ (C═O)

(12)4-(3,4-dichlorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one

yield: quantitative

IR(KBr) of the trifluoroacetate: 3197 (N—H); 1685 (C═O) cm⁻¹

(13) 4-(3-chlorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one

Yield: 98% of theory

R_(f): 0.25 (eluant: ethyl ethanoate/methanol/conc. ammonia 9/1/0.3v/v/v)

(14) 1,3-dihydro-4-(3-hydroxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one

Yield: 90% of theory

R_(f): 0.075 (FM1)

IR(KBr): 1670 (C═O) cm⁻¹

MS: M⁺=259

(15)4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one

Yield: 71% of theory

R_(f): 0.15 (FM1)

IR(KBr): 1701 (C═O) cm⁻¹

MS: M⁺=379

(16)4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one

Yield: 44% of theory

R_(f): 0.71 (FM1; Macherey-Nagel POLYGRAM® SIL G/UV₂₅₄ ready-made filmsfor TLC)

IR(KBr): 1676 (C═O) cm⁻¹

EXAMPLE A2

2,4-dihydro-9-phenyl-2-(4-piperidinyl)-3H-1,2,4-triazol-3-one

a)1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone-(1,1-dimethylethoxycarbonyl)hydrazone

A mixture of 16.0 g (0.05 mol) of1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone, 7.25 g (0.055 mol) oftert. butyl hydrazinoformate and 250 ml of ethanol was refluxed for 1hour. The solvent was distilled off in vacuo, the oily residue remainingwas triturated with diethylether. The crystalline precipitate thusformed was suction filtered and washed with a little diethylether. Afterthe product had been dried in vacuo 21.7 g (99.7% of theory) ofcolourless crystals were obtained, m.p. 156-158° C. (decomposition).

b)N-(1,1-dimethylethoxycarbonyl)-N′-[1-(9H-fluoren-9-yl-methoxycarbonyl)-4-piperidinyl]-hydrazine

A solution of 21.7 g (0.05 mol) of1-(9H-fluoren-9-ylmethoxy-carbonyl)-4-piperidinone-(1,1-dimethylethoxycarbonyl)-hydrazonein 200 ml of glacial acetic acid was hydrogenated in the presence of 2.0g platinum (IV) oxide at room temperature and 3 bar of hydrogen pressureuntil the calculated volume of hydrogen had been taken up. The catalystwas filtered off, the filtrate was evaporated down in vacuo and theresidue was dissolved in a little diethylether. The crystalsprecipitated after standing for 3 hours at room temperature were suctionfiltered, washed with a little diethylether and dried in vacuo at roomtemperature. 21.8 g (99.6% of theory) of colourless crystals of m.p.135-137° C. and R_(f)=0.235 (eluant 3) were obtained.

ESI-MS: (M+H)⁺=438

c)[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]hydrazine-hydrochloride

21.8 g (0.0498 mol) ofN-(1,1-dimethylethoxycarbonyl)-N′-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazinewere dissolved in 100 ml of trifluoroacetic acid and stirred for 1 hourat room temperature. The excess trifluoroacetic acid was removed invacuo, the residue was dissolved in 50 ml of water and made alkalinewith 10% aqueous sodium carbonate solution. The solution was extractedthoroughly with dichloromethane, the combined extracts were dried overmagnesium sulphate and evaporated down in vacuo. The residue thusobtained was taken up in ethyl acetate and converted into thehydrochloride by the addition of ethereal hydrogen chloride solution.After recrystallisation from anhydrous ethanol 6.2 g (33.3% of theory)of colourless crystals of melting point 160-162° C. were obtained.

C₂₀H₂₃N₃O₂+HCl (373.88) Calculated: C, 64.25; H, 6.47; N, 11.24; Cl,9.48. Found: 64.14; 6.46; 10.99; 9.46.

d)2,4-dihydro-5-phenyl-2-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one

The solutions of 5.56 g (0.0165 mol) of[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine in 60 ml oftetrahydrofuran and 3.7 g (0.0177 mol) ofN-(ethoxycarbonyl)-benzothionamide in 30 ml of tetrahydrofuran werecombined and refluxed for 1 hour, whereupon hydrogen sulphide wasreleased. The solvent was distilled off in vacuo, the oily residueremaining was boiled with a little acetonitrile. The mixture was allowedto cool, then additionally cooled from outside with ice water and theresulting precipitate was suction filtered. 4.0 g (52% of theory) ofcolourless crystals were obtained, melting point 142° C. and R_(f)=0.38(eluant 4).

IR (KBr): 1685.7 cm⁻¹ (C═O)

e) 2,4-dihydro-5-phenyl-2-(4-piperidinyl)-3H-1,2,4-triazol-3-one

A mixture of 9.0 g (0.0193 mol) of2,4-dihydro-5-phenyl-2-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one,50 ml of tetrahydrofuran and 70 ml of diethylamine was stirred at roomtemperature until the end of the reaction monitored by thin layerchromatography. The solvent was removed in vacuo, the residue remainingwas mixed with 300 ml of water and subjected to ultrasound treatment for30 minutes. The insoluble matter was separated off by suction filteringand the aqueous filtrate was evaporated down in vacuo. The residue thusobtained was boiled with a little methanol and after cooling it wassuction filtered. After drying 0.58 g (12.3% of theory) of colourlesscrystals of melting point 294° C. (D) and R_(f)=0.1 (eluant 1) wereobtained.

IR (KBr): 1681.8 cm⁻¹ (C═O)

EXAMPLE A3

Preparation of compounds of general structure:

3,4-dihydro-3-(4-piperidinyl)-2-(1H)-pyrido[2,3-d]-pyrimidinone

a) N-(2-Pyridinyl)-2,2-dimethylpropanamide

To a solution of 94.1 g (1.0 mol) of 2-aminopyridine and 173 ml (1.25mol) of triethylamine in 400 ml of dichloromethane were added dropwise,whilst cooling with ice water, 132.5 g (1.099 mol) of pivaloyl chloridein 150 ml of dichloromethane. The mixture was stirred for 2 hours atroom temperature and filtered to remove the triethylamine hydrochlorideformed. The filtrate was washed with water and twice with 5% aqueoussodium hydrogen carbonate solution, then dried over sodium sulphate.After working up in the usual way 157.5 g (88.4% of theory) ofcolourless crystals of melting point 74-76° C. were obtained.

The following was obtained in the same way:

N-(4-Pyridinyl)-2,2-dimethylpropanamide

Yield: 74% of theory

Mp. 137-140° C. (diisopropylether)

IR (KBr): 1687 cm⁻¹ (C═O)

b) N-(-formyl-2-pyridinyl)-2,2-dimethylpropanamide

Whilst maintaining a reaction temperature of −78° C., 781 ml (1.25 mol)of a 1.6-molar solution of n-butyllithium in n-hexane were addeddropwise to a solution of 89.1 g (0.5 mol) ofN-(2-pyridinyl)-2,2-dimethylpropanamide in 300 ml of anhydroustetrahydrofuran. The mixture was allowed to heat slowly up to 0° C. andstirred for 3 hours at this temperature. Then the mixture was againcooled to −78° C. and whilst maintaining this temperature the solutionof 109.6 g (1.5 mol) of dimethyformamide in 150 ml of anhydroustetrahydrofuran was added dropwise thereto. The mixture was allowed tocome up to 0° C. and then stirred into 1 l of ice water. It wasinitially acidified with 12% aqueous hydrochloric acid, then madealkaline by the addition of solid potassium carbonate and extractedthoroughly with diethylether. The combined ether extracts were driedover sodium sulphate and evaporated down. The crystalline residue, afterrecrystallisation from diisopropylether, had an m.p. of 83° C. Yield:94.0 g (91.2% of theory).

The following were obtained in the same way:

(1) N-(4-formyl-3-pyridinyl)-2,2-dimethylpropanamide

Yield: 52% of theory

R_(f): 0.5 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)

IR (KBr) of the hydrochloride: 1695 cm⁻¹ (C═O)

MS: M⁺=206

(2) N-(3-formyl-4-pyridinyl)-2,2-dimethylpropanamide

The reddish oil obtained in a quantitative yield was further processedwithout more purification

c)N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-2-pyridinyl]-2,2-dimethylpropanamide

A solution of 8.2 g (0.0398 mol) ofN-(3-formyl-2-pyridinyl)-2,2-dimethylpropanamide and 7.6 g (0.04 mol) of4-amino-1-(phenylmethyl)piperidine in 80 ml of methanol was combined inbatches with a total of 1.7 g (0.045 mol) of sodium borohydride andrefluxed for a total of 24 hours. The solvent was removed in vacuo, theresidue was distributed between water and ethyl acetate. The organicphase was dried over sodium sulphate and freed from solvent. The residuewas triturated with diisopropylether and suction filtered. 6.0 g (39.6%of theory) of colourless crystals of melting point 138° C. wereobtained.

The following were obtained in the same way:

(1)N-[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-pyridinyl]-2,2-dimethylpropanamide

Yield: 94% of theory

R_(f): 0.4 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)

The yellowish oil was used in the following stage without furtherpurification

(2)N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-4-pyridinyl]-2,2-dimethylpropanamide

Yield: 11.6% of theory

IR(KBr): 1689 (C═O) cm⁻¹

d) 2-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]-amino]methyl]pyridine

A mixture of 6.0 g (0.0158 mol) ofN-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-2-pyridinyl]-2,2-dimethylpropanamideand 100 ml of conc. hydrochloric acid was refluxed for 3 hours. Themixture was evaporated down in vacuo, the residue remaining wasdissolved in a little water and made alkaline by the addition of solidpotassium carbonate. It was extracted thoroughly with ethyl acetate, thecombined extracts were dried over sodium sulphate and evaporated down invacuo. The residue was thoroughly triturated with diisopropylether andyielded 4.2 g (89.7% of theory) of colourless crystals of melting point114° C.

The following were obtained in the same way:

(1) 3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]pyridine

Yield: 96% of theory

R_(f): 0.42 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)

The yellowish oil was used in the following stage without furtherpurification

(2) 4-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]pyridine

Yield: quantitative

The yellowish oil was used in the following stage without furtherpurification

e)3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone

A mixture of 4.2 g (0.0142 mol) of2-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine, 2.4g (0.0148 mol) of N,N′-carbonyldiimidazole and 50 ml ofdimethylformamide was heated to 100° C. for 30 minutes. The still warmmixture was stirred into 300 ml of ice water, the precipitate formed wassuction filtered and recrystallised from acetonitrile. After drying invacuo 4.5 g (98.3% of theory) of colourless crystals of melting point187° C. were obtained.

The following were obtained in the same way:

(1)3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[3,4-d]-pyrimidinone

Colourless crystals

Yield: 33% of theory

IR (KBr): 1676 cm⁻¹ (C═O)

MS: M⁺=322

(2)3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[4,3-d]-pyrimidinone

Mp. 155° C. (D)

Yield: 99% of theory

IR (KBr): 1680 cm⁻¹ (C═O)

f) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone

A solution of 4.7 g (0.0146 mol) of3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinonein 50 ml of methanol was hydrogenated at a temperature of 50° C. and inthe presence of 2.0 g of 20% palladium/charcoal until the uptake ofhydrogen ceased. After removal of the catalyst and solvent 3.3 g (97.3%of theory) of a colourless oil of R_(f)=0.35 (FM1) were obtained.

IR (KBr): 1660.6 cm⁻¹ (C═O)

The following were obtained in the same way:

(1) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[3,4-d]-pyrimidinone

Colourless crystals

Yield: 95% of theory

IR (KBr): 1662 cm⁻¹ (C═O)

MS: M⁺=232

(2) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[4,3-d]-pyrimidinone

Yellowish resin

Yield: 97% of theory

IR (KBr): 1672 cm⁻¹ (C═O)

R_(f): 0.12 (FM1)

EXAMPLE A4

Methyl 3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate

a) (E)-1-(dimethylamino)-2-[4-(methoxycarbonyl)-2-nitrophenyl]ethene

A mixture of 98.3 g (0.504 mol) of methyl 4-methyl-3-nitrobenzoate, 78.0g (0.655 mol) of N,N-dimethylformamide dimethylacetal and 1 1 ofdimethylformamide was heated to 140° C. for 3 hours. The solvent wasdistilled off in vacuo, the residue was triturated thoroughly with 1 1methanol. After drying in vacuo 119.5 g (94.7% of theory) of a redamorphous substance was obtained, which was further processed withoutany more purification.

b) 4-(Methoxycarbonyl)-2-nitrobenzaldehyde

To a mixture of 119.5 g (0.478 mol) of(E)-1-(dimethylamino)-2-[4-(methoxycarbonyl)-2-nitrophenyl]-ethene and1.3 l of water/tetrahydrofuran mixture (1/1 v/v) were added, in batches,308.0 g (1.44 mol) of sodium metaperiodate, whilst the reactiontemperature was regulated at under +30° C. by external cooling with icewater. The mixture was stirred for a further 2.5 hours at roomtemperature and then filtered. The precipitate was thoroughly washedwith ethyl acetate. The organic phase was separated off, the aqueousphase was thoroughly extracted with ethyl acetate. The combined ethylacetate phases were dried over sodium sulphate and evaporated down invacuo. The oil which crystallised after one day was further processedwithout any more purification. Yield: 87 g (87% of theory).

c) Methyl4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-nitrobenzoate

To a solution of 41.0 g (0.215 mol) of4-amino-1-(phenylmethyl)-piperidine and 45.0 g (0.215 mol) of4-(methoxycarbonyl)-2-nitrobenzaldehyde in 1 l methanol were added inbatches, at room temperature, 8.3 g (0.22 mol) of sodium borohydride andthe mixture was then stirred for 30 minutes at the same temperature. Themixture was stirred into 1 l of ice water and thoroughly extracted withtert. butyl-methylether. The combined extracts were dried over sodiumsulphate and evaporated down in vacuo, the residue was dissolved in aslittle methanol as possible and converted into the hydrochloride bytreatment with methanolic hydrogen chloride solution. The crystallinesalt was suction filtered, washed with methanol and diethylether, thentaken up in water and made alkaline with saturated aqueous potassiumcarbonate solution. The mixture obtained was extracted thoroughly withethyl acetate, the combined ethyl acetate extracts were dried oversodium sulphate and evaporated down. 58.2 g (70.6% of theory) of abrownish-yellow oil were obtained, which was further processed withoutany more purification.

d) Methyl3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-benzoate

A solution of 58.0 g (0.151 mol) of methyl4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-nitrobenzoate in 800ml of methanol was hydrogenated in the presence of 10 g of 5%rhodium/charcoal for 7 hours at room temperature. The catalyst wasfiltered off, the filtrate was evaporated down in vacuo. 50.0 g (93.7%of theory) of colourless crystals were obtained, which were furtherprocessed without any more purification.

e) Methyl3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-oxoquinazolin-7-carboxylate

Prepared analogously to Example A3e) from methyl3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-benzoate andN,N′-carbonyl-diimidazole in a yield of 66.3% of theory.

Slightly yellowish crystals.

IR (KBr): 1714.6; 1664.5 cm⁻¹ (C═O)

f) Methyl3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazolin-7-carboxytate

A solution of 35.5 g (0.0936 mol) of methyl3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-oxoquinazolin-7-carboxylatein 400 ml of methanol was hydrogenated in the presence of 5 g of 10%palladium/charcoal for 5 hours at 50° C. The catalyst was filtered off,the filtrate was evaporated down in vacuo. The residue was trituratedwith 150 ml of ethyl acetate and then suction filtered. After drying invacuo 20.4 g (75.3% of theory) of colourless crystals were obtained,which were further processed without any more purification.

IR (KBr): 1718.5; 1672.2 cm⁻¹ (C═O)

The following were prepared analogously:

(1) 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone

R_(f): 0.3 (FM1)

IR (KBr): 1662.5 cm⁻¹ (C═O)

(2) 3,4-dihydro-8-methoxy-3-(4-piperidinyl)-2(1H)-quinazolinone

R_(f): 0.35 (FM1)

(3) 3,4-dihydro-6,7-dimethoxy-3-(4-piperidinyl)-2(1H)-quinazolinone

R_(f): 0.40 (FM1)

EXAMPLE A5

3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,4-d]pyrimidin-2-one-trifluioroacetate

a) Methyl 4-(ethoxycarbonylamino)-thiophene-3-carboxylate

A mixture of 50.0 g (0.258 mol) of methyl4-aminothiophen-3-carboxylate-hydrochloride, 700 ml of toluene, 26 g(0.257 mol) of triethylamine and 27 ml (0.283 mol) of ethylchlorocarbonate was refluxed for 5 hours. The insoluble matter wasfiltered off, the filtrate was evaporated down in vacuo and the residuewas crystallised from petroleum ether. 59.0 g (99.8% of theory) ofcolourless crystals of melting point 52° C. were obtained.

In the same way, crystalline methyl3-(ethoxycarbonylamino)-thiophen-2-carboxylate was obtained from methyl3-aminothiophene-2-carboxylate and ethyl chlorocarbonate in a yield of98.7% of theory.

IR (KBr): 1739.7; 1622 cm⁻¹ (C═O, C═C)

b) 4-(ethoxycarbonylamino)-thiophene-3-carboxaldehyde

Into an ice-cold suspension of 12.9 g (0.34 mol) of lithium aluminiumhydride in 800 ml of tert. butyl-methylether was added dropwise, at areaction temperature of about 0° C., a solution of 59.1 g (0.258 mol) ofmethyl 4-(ethoxycarbonylamino)-thiophene-3-carboxylate in 200 ml oftert. butyl-methyl-ether, and the mixture was then stirred for a further2 hours at 10° C. Then 13 ml of water, 13 ml of 2N aqueous sodiumhydroxide solution and 39 ml of water were added dropwise one afteranother and the mixture was stirred for 1 hour at room temperature. Itwas filtered, and 500 g of activated manganese (IV) oxide were added inbatches to the filtrate with stirring. After the completion of thereaction, which could be monitored by thin layer chromatography, themixture was filtered again and the filtrate was then evaporated down invacuo. The crystalline residue which solidified was further processedwithout any more purification. yield: 28.2 g (54.9% of theory).

In the same way 3-(ethoxycarbonylamino)-thiopbene-2-carboxaldehyde wasobtained from methyl 3-(ethoxycarbonylamino)-thiophene-2-carboxylate ina yield of 71.9% of theory.

c)4-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophene

A mixture of 28.2 g (0.142 mol) of4-(ethoxycarbonyl-amino)-thiophene-3-carboxaldehyde, 28.2 g (0.141 mol)of 4-amino-1-(1,1-dimethyl-ethoxycarbonyl)piperidine and 300 ml oftoluene was refluxed using a water separator until water formation hadceased. The solvent was removed in vacuo, the residue was dissolved in300 ml of methanol and at room temperature combined batchwise with 5.5 g(0.145 mol) of sodium borohydride. The mixture was stirred for a furtherhour at room temperature, then evaporated down in vacuo and the residuewas distributed between water and tert. butyl-methylether. The organicphase was dried over sodium sulphate and freed from solvent in vacuo.The oily residue was further processed without purification.

Yield: 54.0 g (99.9% of theory).

In the same way2-[[[1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophenewas obtained from 3-(ethoxycarbonylamino)-thiophene-2-carboxaldehyde,4-amino-1-(1,1-dimethylethoxycarbonyl)piperidine and sodium borohydridein a yield of 100% of theory.

IR (KBr): 1728.1; 1693.4 cm⁻¹ (C═O)

d)3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,4-d]pyrimidin-2-one

A solution of 54.0 g (0.141 mol) of4-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophenein 300 ml of dimethylformamide was refluxed for 4 hours. After the endof the reaction, which could be monitored by thin layer chromatography,the still warm mixture was stirred into 1 l of ice water. Thecrystalline precipitate was suction filtered and dried at 30° C. in acirculating air drier.

Yield: 47.5 g (99.8% of theory).

In the same way3,4-dihydro-3-[1-(1,1-dimethyl-ethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,2-d]pyrimidin-2-onewas obtained from2-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonyl-amino)-thiophenein a yield of 71% of theory. Colourless crystals of melting point 200°C. (acetonitrile).

IR (KBr): 1683.8; 1654.8 cm⁻¹ (C═O)

e)3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,4-d]pyrimidin-2-one-trifluoroacetate

A mixture of 10.0 g (0.0296 mol) of3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,4-d]pyrimidin-2-oneand 50 ml of trifluoroacetic acid was stirred at room temperature for 30minutes. The residue remaining after removal of the excesstrifluoroacetic acid was triturated with diethylether and suctionfiltered. 5.8 g (55.8% of theory) of colourless crystals were obtained,which were used without further purification.

IR (KBr): 1664.5 cm⁻¹ (C═O)

In the same way, crystalline3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,2-d]pyrimidin-2-one-trifluoracetatewas obtained from3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno-[3,2-d]pyrimidin-2-oneand trifluoroacetic acid in a yield of 100% of theory.

IR (KBr): 1685.7; 1656.8 cm⁻¹ (C═O)

EXAMPLE A6

3,4-dihydro-3-(4-piperidinyl)-2(1H)quinolone-hydrochloride

A mixture of 1.1 g (4.949 mmol) of 3-(4-pyridinyl)-2(1H)-quinolone (D.R. Bragg and D. G. Wibberley, J. Chem. Soc. 1961, 5074-5077), 100 ml ofethanol, 5 ml (5 mmol) of iN hydrochloric acid and 0.2 g platinum (IV)oxide was hydrogenated for 4 hours at room temperature. The catalyst wasfiltered off, the filtrate evaporated down in vacuo and the residue wastriturated with isopropanol. The precipitated crystals were suctionfiltered, washed with isopropanol and diethylether and dried in vacuo.Yield: 0.64 g (56.2% of theory).

IR (KBr): 1666.4 cm⁻¹ (C═O)

MS: M⁺=230 m/e =146, 84

EXAMPLE A7

3-(4-Piperidinyl)-2(1H)-quinolone

A mixture of 8.6 g (0.0387 mol) of 3-(4-pyridinyl)-2(1H)-quinolone, 1.21 of ethanol, 39 ml (0.039 mol) of 1N hydrochloric acid and 8.0 g of 10%palladium/charcoal was hydrogenated at a temperature of 40° C. untilabout 0.08 mol of hydrogen had been taken up. The mixture was freed fromcatalyst, the filtrate was evaporated down in vacuo, the residue wastaken up in 200 ml of water and made ammoniacal. Common salt was addedup to saturation point and the mixture was continuously extracted withdichloromethane using a perforator. The dichloromethane phase wasevaporated down, the residue remaining was separated from by-products bychromatography over silica gel using FM1 as eluant. The appropriatefractions were combined, freed from solvent, dissolved in a littleisopropanol and converted with ethanolic hydrogen chloride solution intothe hydrochloride. Colourless crystals. Yield: 2.68 g (26.2% of theory).

MS: M⁺=228

IR (KBr): 1651 cm⁻¹ (C═O)

EXAMPLE A8

5-chloro-3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone

An ice-cold solution of 6.3 g (0.0177 mol) of5-chloro-3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-quinazolinone(prepared analogously to Example A4e)) in 50 ml of dichloromethane wasmixed dropwise with 3.34 g (0.0234 mol) of α-chloroethyl chlorocarbonatewhilst maintaining a reaction temperature of 0° C., after which themixture was allowed to come back slowly to room temperature. Thereaction mixture was evaporated down in vacuo, the residue was taken upin 50 ml of methanol and refluxed for 4 hours. After cooling, thecolourless precipitate formed was suction filtered. Yield: 2.0 g (42.5%of theory).

IR (KBr): 1666.4 cm⁻¹ (C═O)

EXAMPLE A9

6-bromo-3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone-hydrohromide

To a solution of 6.16 g (0.075 mol) of sodium acetate and 11.565 g (0.05mol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a mixtureof 150 ml of glacial acetic acid and 35 ml of water a solution of 8.8 g(0.055 mol) of anhydrous bromine in 20 ml of glacial acetic acid wasadded dropwise, with stirring and whilst maintaining a reactiontemperature of 13 to 15° C. The mixture was filtered and the filtratewas evaporated down in vacuo. To remove any inorganic components theresidue was taken up five times in 50 ml of dichloromethane, filteredand evaporated down, then triturated with a little acetonitrile,whereupon crystallisation occurred. The crystals were suction filtered,washed with acetonitrile/diethylether (1/1 v/v) and after drying invacuo 5.5 g of colourless crystals of melting point 288° C.(decomposition) were obtained. By working up the mother liquors afurther 4.5 g of material of the same quality was obtained. Total

yield: 10.0 g (51% of theory).

C₁₃H₁₇Br₂N₃O (391.10) Calculated: C, 39.92; H, 4.38; Br, 40.86; N,10.74. Found: 39.72; 4.36; 41.56; 10.24.

IR (KBr): 1670.3 cm−1 (C═O)

EXAMPLE A10

3-(4-piperidinyl)-2,4 (1H,3H)-quinazolindione

a)2-amino-N-[1-(phenylmethyl)-4-piperdidinyl]-benzamide

To an ice-cold solution of 28 ml (134 mmol) of4-amino1-(phenylmethyl)piperidine in 200 ml of tetrahydrofuran wereadded, batchwise, 21.9 g (134 mmol) of isatoic acid anhydride. Theresulting suspension was stirred for 2½ hours at room temperature and 2½hours at reflux temperature, then freed from solvent. The residue wasdissolved in 100 ml of hot ethanol, the resulting solution was filteredwhilst hot after the addition of 5 g of activated charcoal. The crystalmass precipitated after cooling was suction filtered, washed withdiisopropyl-ether and dried in vacuo at 50° C. 28.3 g of colourlesscrystals were obtained. A further 5.1 g of a product of the same qualitywere isolated from the combined mother liquors. Total

yield: 33.4 g (80.6% of theory).

IR (KBr): 1620 cm⁻¹ (C═O)

MS: M⁺=309

b) 3-[1-(phenylmethyl)-4-piperidinyl]-2,4(1H,3H)-quinazolindione

Prepared analogously to Example A3e) from2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzamide andN,N′-carbonyldiimidazole in a yield of 97.8% of theory. Colourlesscrystals of melting point 223° C.

IR (KBr): 1720; 1647 cm⁻¹ (C═O)

MS: M⁺=335

c) 3-(4-piperidinyl)-2,4(1H,3H)-quinazolindione

Prepared analogously to Example A3f) from3-[1-(phenylmethyl)-4-piperidinyl]-2,4(1H,3H)-quinazolindione byhydrogenolysis in the presence of palladium/charcoal in a yield of 70%of theory.

R_(f): 0.075 (FM1)

IR (KBr): 1703; 1657 cm⁻¹ (C═O)

EXAMPLE A11

3,4-dihydro-3-[1-(4-piperidinyl)-4-piperidinyl]-2(1H)-quinazolinone

a)3,4-dihydro-3-[1-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-2(1H)-qinazolinone

A mixture of 5.75 g (0.0249 mol) of3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone, 4.75 g (0.0251 mol)of 1-(phenylmethyl)-4-piperidinone and 100 ml of ethanol was treated for30 minutes in an ultrasound bath, then mixed with 9.5 ml (0.031 mol) oftitanium (IV) isopropoxide, whereby after 10 minutes a crystal mass wasformed. Then heating was continued using the ultrasound bath for afurther 2½ hours to a maximum of 35° C., the mixture was allowed to coolto room temperature and 1.05 g (0.0167 mol) of sodium cyanoborohydridewere then added in batches, whilst maintaining the pH at 5-6 usingdilute methanolic hydrogen chloride solution, and it was then kept for24 hours at room temperature. After this time another 1.05 g (0.0167mol) of sodium cyanoborohydride were added and the same procedure wasused as above. After a total of 48 hours reaction time the mixture wasdecomposed by the addition of water and worked up in the usual way. Thecrude product obtained was purified by column chromatography over silicagel using FM4 as eluant. 7.05 g (70% of theory)of a colourlesscrystalline substance were obtained.

In the same wayexo-4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-(phenylmethyl)piperazinewas obtained from tropinone and 1-(phenylmethyl)piperazine in a yield of48.9% of theory. Colourless, amorphous substance, R_(f)=0.36 (FM1).

b) 3,4-dihydro-3-[1-(4-piperidinyl)-4-piperidinyl]-2(1H)-quinazolinone

Prepared analogously to Example A3f) from3,4-dihydro-3-[1-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-2(1H)-quinazolinoneby hydrogenolysis, but using Pearlman's catalyst, in a yield of 92% oftheory. Colourless crystals, R_(f)=0.48 (Macherey-Nagel, POLYGRAM® SILG/UV₂₅₄ ready-made films for TLC; eluant:dichloromethane/methanol/cyclohexane/conc. ammonia 68/20/10/5 v/v/v/v).

IR (KBr): 1660.6 cm⁻¹ (C═O)

MS: M⁺=314

EXAMPLE A12

3-(4-piperidinyl)-3,4,4a,5,6,7,8,8a-octahydro-2(1H)-quinazolinone-acetate

A solution of 5.0 g (17.17 mmol) of3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone-acetate in 70 ml ofmethanol was hydrogenated at room temperature and in the presence of 1.0g rhodium (III) oxide-platinum (IV) oxide hydrate catalyst (46.45%rhodium, 20.15% platinum) until the hydrogen uptake had ceased. Thecatalyst and solvent were removed, the residue was triturated with 10 mlof diisopropylether and a few drops of isopropanol and the resultingcrystals were suction filtered. After drying in vacuo 4.4 g (86.2% oftheory) of colourless crystals were obtained, R_(f)=0.3 (eluant:dichloromethane/methanol/conc. ammonia 7.5/2.5/0.5 v/v/v).

IR (KBr): 1641 cm⁻¹ (C═O)

MS: M⁺=237

EXAMPLE A13

1,1dioxido-2-(4-piperidinyl)-3(4H)-1,2,4-benzothiadiazinone

a) 2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acidamide

Whilst carrying out external cooling with ice water a solution of 44.3 g(0.2 mol) of 2-nitrobenzenesulphonyl chloride in 250 ml of chloroformwas added dropwise to a solution of 38.0 g (0.2 mol) of4-amino1-(phenylmethyl)piperidine and 22.0 g (0.22 mol) of triethylaminein 250 ml of chloroform. After the cooling was stopped the mixture wasstirred for a further 30 minutes at room temperature, the reactionmixture was then extracted twice with 1 l water. The aqueous extractswere extracted once more with 100 ml of dichloromethane, the combinedorganic phases were then dried over sodium sulphate and evaporated downin vacuo. The highly viscous light-brown substance obtained in a yieldof 75.0 g (99.9% of theory) was further processed without any morepurification.

IR (KBr): 3363.7 (NH); 1541.0 (NO₂); 1365.5 (NO₂ or SO₂); 1346.2 (NO₂ orSO₂); 1168.8 (SO₂) cm⁻¹

b) 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acidamide

To a solution of 75.0 g (0.2 mol) of2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amidein 2.0 1 ethanol was added dropwise, at room temperature, a solution of174.0 g (0.828 mol) of sodium dithionite-dihydrate in 700 ml of water.After the heat of the exothermic reaction had died away the mixture wasrefluxed for 4.5 hours, then the ethanol was distilled off and theaqueous phase remaining was extracted thoroughly with dichloromethane.The combined dichloromethane extracts were dried over sodium sulphateand evaporated down, the residue remaining was purified by columnchromatography over silica gel using dichloromethane/methanol/conc.ammonia 80/20/0.25 (v/v/v) as eluant. 6.5 g (8.6% of theory) of a highlyviscous oil were obtained.

IR(KBr): 1319.2, 1153.4 cm⁻¹ (SO₂)

c)1,1-dioxido-2-[1-(phenylmethyl)-4-piperidinyl]-3(4H)-1,2,4-benzothiadiazinone

Prepared analogously to Example A3e) from2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amideand N,N′-carbonyldiimidazole in a yield of 78% of theory. Colourlesscrystals of melting point 169-171° C.

IR(KBr): 1693.4 (C═O); 1359.7, 1340.4, 1188.1 (SO₂) cm⁻¹

d) 1,1-dioxido-2-(4-piperidinyl)-3(4H)-1,2,4-benzothiadiazinone

Prepared analogously to Example A3f), but using Pearlman's catalystinstead of palladium/charcoal, in a yield of 90% of theory. Colourless,amorphous substance.

IR(KBr): 1705.0 (C═O) cm⁻¹

EXAMPLE A14

3,4-dihydro-2,2-dioxido-3-(4-piperidinyl)-2,1,3-benzothiadiazine

a)3,4-dihydro-2,2-dioxido-3-[1-(phenylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazine

A solution of 11.0 g (0.0372 mol) of2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenemethanamine in 200 mlof pyridine was added dropwise within 1.5 hours and at refluxtemperature to a solution of 3.4 g (0.0354 mol) of sulphamide in 200 mlof pyridine and the mixture was then refluxed for 6 hours. The mixturewas freed from solvent, the residue was purified by columnchromatography using ethyl acetate/methanol 9/1 (v/v) as eluant. 5.5 g(43.5% of theory) of a colourless amorphous substance were obtained.

IR(KBr): 1344.3, 1166.9 cm⁻¹ (SO₂)

b) 3,4-dihydro-2,2-dioxido-3-(4-piperidinyl)-2,1,3-benzothiadiazine

Prepared analogously to Example A3f) from3,4-dihydro-2,2-dioxido-3-[1-(phenylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazineby catalytic hydrogenation in the presence of palladium/charcoal in aquantitative yield. Colourless, amorphous substance.

IR(KBr): 1263.3, 1105.1 cm⁻¹ (SO₂)

EXAMPLE A15

D,L-4-phenyl-1-(4-piperidinyl)-imidazolidine-2,5-dione

a)N²-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide

A mixture of 10.0 g (0.0398 mol) ofN²-(1,1-dimethylethoxycarbonyl)-D,L-phenylglycine, 7.57 g (0.0398 mol)of 4-amino-1-(phenylmethyl)piperidine, 10 ml of triethylamine, 12.8 g(0.0399 mol) of TBTU and 5.4 g (0.0353 mol) ofN-hydroxybenzotriazole-hydrate in 200 ml of THF-DMF mixture (1/1 v/v)was stirred overnight at room temperature. The residue remaining afterremoval of the solvent was taken up in ethyl acetate, washed withsaturated sodium hydrogen carbonate solution, dried over sodium sulphateand evaporated down in vacuo. 14.8 g (87.8% of theory) of a colourless,amorphous substance were obtained.

IR(KBr): 1701.1, 1676.0, 1652.9 cm⁻¹ (C═O)

AnalogouslyN²-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]D,L,-phenylalaninamidewas obtained from N²-(1,1-dimethylethoxycarbonyl)-D,L-phenylalanine and4-amino-1-(phenylmethyl)piperidine in a yield of 85% of theory.Colourless, amorphous substance, R_(f)=0.83 (eluant:dichloromethane/cyclohexane/metha-nol/conc. ammonia=70/15/15/2 v/v/v/v).

IR(KBr): 1683.8, 1651.0 cm⁻¹ (C═O)

b)N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide-bis-trifluoroacetate

Prepared analogously to Example A5e) fromN²-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamideand trifluoroacetic acid in a quantitative yield. Colourless, amorphoussubstance , R_(f)=0.56 (FM1).

AnalogouslyN-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenyalaninamide-bis-trifluoracetatewas obtained fromN2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamidein a yield of 92% of theory.

IR(KBr): 1670.3 cm⁻¹ (C═O)

c)D,L-4-phenyl1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione

Prepared analogously to Example A3e) fromN-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide andN,N′-carbonyldiimidazole in a yield of 57.3% of theory. Colourlesscrystals,

R_(f)=0.68.

IR(KBr): 1774.4, 1712.7 cm⁻¹ (C═O)

AnalogouslyD,L-4-(phenylmethyl)-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dionewas obtained fromN-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide in a yield of93% of theory. Colourless, fine crystals, R_(f)=0.6 (eluant:dichloromethane/methanol/cyclohexane/conc. ammonia 7/1.5/1.5/0.2v/v/v/v).

IR(KBr): 1764.8, 1708.8 cm⁻¹ (C═O)

MS: M⁺=363

d) D,L-4-phenyl1-(4-piperidinyl)-imidazolidine-2,5-dione

Prepared analogously to Example A3f) fromD,L-4-phenyl1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dioneby hydrogenolysis in the presence of palladium/charcoal in a yield of84.3% of theory. Colourless, amorphous substance, R_(f)=0.5.

IR(KBr): 1766.7, 1706.9 cm⁻¹ (C═O)

AnalogouslyD,L-4-(phenlmethyl)-1-(4-piperidinyl)-imidazolidine-2,5-dione wasobtained fromD,L-4-(phenylmethyl)-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione.Colourless crystals, R_(f)=0.24 (eluant:dichloromethane/methanol/cyclohexane/conc. ammonia=7/1.5/1.5/0.2v/v/v/v).

IR(KBr): 1766.7, 1705.0 cm⁻¹ (C═O)

EXAMPLE A16

1,3-dihydro-3-(4-piperidinyl)-2(2H)-imidazo[4,5-c]quinolone

a) 1-[2-(acetlyamino)phenyl]-2-bromoethanorne

45.0 g (0.282 mol) of dry bromine were added dropwise to a boilingsolution of 50.0 g (0.282 mol) of 1-[2-(acetylamino)phenyl]ethanone in400 ml of chloroform at room temperature. The solvent was distilled off,the residue was distributed between dichloromethane and saturatedice-cold sodium hydrogen carbonate solution. The organic phase was driedover sodium sulphate, evaporated down in vacuo, the residue wastriturated with diethylether and suction filtered. After drying in vacuo35.4 g (49% of theory) of colourless crystals were obtained, R_(f)=0.48(eluant: petroleum ether/ethyl acetate 2/1 v/v).

IR(KBr): 1685.69, 1664.47 cm⁻¹ (C═O)

MS: M⁺=255/257 (Br)

b)4-[2-(acetylamino)phenyl]-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-one

To a solution of 26.3 g (0.138 mol) of 4-amino1-(phenylmethyl)piperidineand 17.8 g (0.138 mol) of DIEA in 300 ml of dichloromethane was addeddropwise a solution of 35.4 g (0.138 mol) of1-[2-(acetylamino)phenyl]-2-bromoethanone in 150 ml of dichloromethaneand the mixture was kept for a further 2 hours at room temperature. Withexternal cooling with ice 13.5 g (0.20 mol) of sodium cyanate and 12 mlof glacial acetic acid were then added and the mixture was stirredovernight in a thawing ice bath. It was washed with water and saturatedsodium hydrogen carbonate solution, dried over sodium sulphate and freedfrom solvent. The residue was triturated with 50 ml of ethylacetate-methanol mixture (9/1 v/v), the resulting crystals were suctionfiltered, washed with ethyl acetate and dried in vacuo. 37.0 g (68.7% oftheory) of colourless crystals were obtained, R_(f)=0.41 (eluant:dichloromethane/methanol 9/1 v/v)

IR(KBr): 1678 cm⁻¹ (C═O)

MS: M⁺=390 (Br)

c)4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-pipleridinyl]-2H-imidazol-2-one

A mixture of 3.0 g (7.68 mmol) of4-[2-(acetylamino)phenyl]-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one,50 ml of 5 N sodium hydroxide solution and 25 ml of ethanol was refluxedfor 3 hours. After cooling the organic phase was separated off, driedover sodium sulphate and evaporated down in vacuo. A colourlessamorphous substance was obtained in a quantitative yield, R_(f)=0.53(eluant: dichloromethane/methanol 9/1 v/v).

d)1,3-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(2H)-imidazo[4,5-c]quinolone

A solution of 2.67 g (7.66 mmol) of4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-onein 50 ml of chloroform was mixed with 3.0 g of paraformaldehyde andrefluxed for 3.5 hours. The residue remaining after evaporation of thesolvent was taken up in 100 ml of methanol and acidified with methanolichydrogen chloride solution. After stirring for one hour at roomtemperature the mixture was poured into 300 ml of saturated sodiumhydrogen carbonate solution. The resulting mixture was extractedthoroughly with ethyl acetate, the combined extracts were dried oversodium sulphate and evaporated down in vacuo. The residue was purifiedby column chromatography over silica gel using FM4 as eluant. From theappropriate fractions 0.5 g (18.2% of theory) of a colourless, amorphoussubstance were isolated, R_(f)=0.24 (FM4)

IR(KBr): 1689 cm⁻¹ (C═O)

MS: M⁺=358 (Br)

e) 1,3-dihydro-3-(4-piperidinyl)-2(2H)-imidazo[4,5-c]quinolone

Prepared analogously to Example A3f) from1,3-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(2H)-imidazo[4,5-c]quinoloneby hydrogenolysis in the presence of palladium/charcoal in a yield of98.5% of theory. Colourless crystals, R_(f)=0.63 (FM1).

EXAMPLE A17

Preparation of β-(methoxycarbonyl)-arenebutanoic acids

3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid

a) 4-(phenylmethoxy)-benzaldehyde

To a solution of 36.6 g (0.3 mol) of 4-hydroxybenzaldehyde in 100 ml ofethanol were added dropwise, one after another, a solution of 12.0 g(0.3 mol) of sodium hydroxide in 100 ml of water and a solution of 36.5ml of (0.307 mol) of benzylbromide in 100 ml of ethanol and the mixturewas then kept for 1 hour at 50° C. The ethanol was extensively distilledoff, finally in vacuo, the remaining aqueous emulsion was dividedbetween water and ethyl acetate. The ethyl acetate phase was dried oversodium sulphate and evaporated down in vacuo. The residue remainingcrystallised on trituration with petroleum ether and was recrystallisedfrom diisopropylether. 48.0 g (75.4% of theory) of colourless crystalsof melting point 118-122° C. were obtained.

b) 3-(methoxycarbonyl)-4-[(4-phenylmethoxy)phenyl]-3-butenoic acid

To a freshly prepared solution of 2.3 g (0.1 mol) of sodium in 300 ml ofanhydrous methanol were added 14.6 g (0.1 mol) of dimethyl succinate andafter half an hour's stirring a solution of 21.2 g (0.1 mol) of4-(phenylmethoxy)-benzaldehyde in 100 ml of anhydrous methanol wereadded dropwise. Then the mixture was refluxed for 6 hours, the methanolwas distilled off under normal pressure and the remaining residue waskept for 30 minutes at a reaction temperature of 80° C. The viscousslurry obtained was stirred into 1 l of a glacial acetic acid-watermixture (1/1 v/v), the resulting mixture was extracted thoroughly withethyl acetate. The combined ethyl acetate extracts were in turnextracted with saturated potassium carbonate solution. The potassiumcarbonate extracts were carefully acidified with acetic acid and thenextracted thoroughly with ethyl acetate. These extracts were washed withwater, dried over sodium sulphate and freed from solvent in vacuo. Theresidue was purified by column chromatography over silica gel usingdichloromethane/petroleum ether/glacial acetic acid 25/74/1 (v/v/v). Thecolourless, partly crystallised mixture of diastereomers was obtained ina yield of 16.0 g (49% of theory) . R_(f)=0.68 (eluant: ethylacetate/petroleum ether 1:2 v/v).

IR(KBr): 1699.2 cm⁻¹ (C═O)

The following were obtained analogously:

(1) 3-(methoxycarbonyl)-4-[3-(trifluoromethyl)phenyl]1 -3-butenoic acidwas obtained from 3-(trifluoromethyl)benzaldehyde and dimethyl succinatein a yield of 21% of theory.

IR(KBr): 1738, 1726 cm⁻¹ (C═O)

ESI-MS: (M−H)⁻=287 (M+H)⁺=289 (M+Na)⁺=311

(2) 3-(methoxycarbonyl)-4-(1-naphthyl)-3-butenoic acid was obtained from1-naphthaldehyde and dimethyl succinate in a yield of 60% of theory.

Colourless oil

IR(KBr): 1712 cm⁻¹ (C═O)

MS: M⁺=270

(3) 3-(methoxycarbonyl)-4-[3,5-dimethyl-4-phenylmethoxyphenyl]-3-butenicacid was obtained from 3,5-dimethyl-4-phenylmethoxybenzaldehyde anddimethyl succinate in a yield of 66% of theory.

Colourless oil which could be further processed without purification.

(4) 4-(4-amino-3,5-dibromophenyl)-3-(methoxycarbonyl)-3-butenoic acidwas obtained from 4-amino-3,5-dibromobenzaldehyde and dimethyl succinatein a yield of 21% of theory.

(5) 3-(Methoxycarbonyl)-4-(3-phenylmethoxpheny)-1-3-butenoic acid wasobtained from 3-phenylmethoxybenzaldehyde and dimethyl succinate in ayield of 37% of theory.

c) 4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid

Prepared analogously to Example A3f) from3-(methoxycarbonyl)-4-[(4-phenylmethoxy)phenyl]-3-butenoic acid byhydrogenolysis in the presence of palladium/charcoal in a yield of 96%of theory. Colourless oil, R_(f)=0.5 (eluant: ethyl acetate/petroleumether/glacial acetic acid 66.3/33.3/0.4 v/v/v).

The following were obtained analogously:

(1) β-(methoxycarbonyl)-3-(trifluoromethyl)-benzenebutanoic acid wasobtained from3-(methoxycarbonyl)-4-[3-(trifluoromethyl)phenyl]-3-butenoic acid in ayield of 80% of theory. R_(f)=0.59 (eluant: ethyl acetate/petroleumether 1/1/ v/v).

ESI-MS: (M−H)⁻=289

(2) β-(methoxycarbonyl)-1-naphthalinebutanoic acid was obtained from3-(methoxycarbonyl)-4-(1-naphthyl)-3-butenoic acid, however usingplatinum (IV)-oxide as a catalyst, in a yield of 31% of theory.

IR (KBr): 1734, 1711 (C═O) cm⁻¹

MS: M⁺=272

β-(methoxycarbonyl)-1,2,3,4-tetrahydro-1-naphthaline-butanoic acid wasisolated as a by-product in a yield of 8.4% of theory

IR (KBr): 1736, 1712 (C═O) cm⁻¹

MS: M⁺=276

(3) 3,5-dimethyl-4-hydroxy-β-(methoxycarbonyl)-benzene butanoic acid wasobtained from3-(methoxycarbonyl)-4-[3,5-dimethyl-4-phenylmethoxyphenyl]-3-butenoicacid in a yield of 48% of theory.

R_(f)=0.11 (FM1)

IR (KBr): 1716 (C═O) cm⁻¹

MS: M⁺=266

(4) 3-Hydroxy-β-(methoxycarhonyl)-benzene butanoic acid was obtainedfrom 3-(Methoxycarbonyl)-4-(3-phenylmethoxyphenyl)-3-butenoic acid in ayield of 59% of theory.

R_(f)=0.24 (petroleum ether/ethyl acetate/glacial acetic acid 6/4/0.2v/v/v)

IR (KBr): 1714 (C═O) cm⁻¹

MS: M⁺=238

(5) 4-Amino-β-(methoxycarbonyl)-benzene butanoic acid was obtained from3-(methoxycarbonyl)-4-(4-amino-3,5-dibromophenyl)-3-butenoic acid and inthe presence of triethylamine in a quantitative yield.

R_(f)=0.53 (eluant: dichloromethane/methanol/glacial acetic acid90/10/1.5 v/v/v))

IR (KBr): 1728 (C═O) cm⁻¹

MS: M⁺=237

d) 3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid

To a solution of 12.0 g (0.05 mol) of4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 200 ml of glacialacetic acid were added 150 ml of water and 8.0 g sodium acetate and thena solution of 15.58 g (0.0975 mol) of bromine in 60 ml of glacial aceticacid was added dropwise. The mixture was stirred for a further hour atroom temperature, then evaporated down to two thirds in vacuo and theresidue was divided between water and ethyl acetate. The ethyl acetateextracts were washed with water, dried over sodium sulphate andevaporated down in vacuo. After stirring with diisopropylether acolourless crystal was obtained. Yield: 12.0 g (62.2% of theory).R_(f)=0.4 (eluant: ethyl acetate/petroleum ether/glacial acetic acid49.8/49.8/0.4 v/v/v).

IR(KBr): 1724 cm⁻¹ (C═O)

MS: M⁺=394/396/398 (Br₂)

EXAMPLE A18

1-(3 -pyridinyl)piperazine

a) 1-(phenylmethyl)-3-(3 -pyridinyl)piperazine

To a solution of 5.0 g (0.0515 mol) of 3-fluoropyridine and 43.5 ml of1-(phenylmethyl)piperazine in 300 ml of anhydrous diethylether was addeddropwise, at boiling temperature, within 2.5 hours, 56 ml (0.112 mol) ofa 2 molar solution of phenyllithium in a cyclohexane-diethylethermixture (7/3 v/v) and the resulting mixture was then kept at refluxtemperature for a further 4 hours. The crude reaction product obtainedas an oil after working up in the usual way was purified by columnchromatography over silica gel (30-60 μm) using FM1/cyclohexane (7/3v/v)as eluant. 12.0 g (92% of theory) of a colourless oil were obtained,R_(f)0.52 (FM4; Macherey-Nagel, POLYGRAM® SIL G/UV₂₅₄ Pre-coated plasticsheets for TLC)

MS: M⁺=253

b) 1-(3-Pyridinyl)piperazine

Prepared analogously to Example A3f) from1-(phenylmethyl)-3-(3-pyridinyl)piperazine by hydrogenolysis in thepresence of palladium/charcoal in a yield of 55% of theory. Colourlessoil, R_(f)0 .35 (FM1).

IR(KBr): 1652.9 cm⁻¹ (C═N)

EXAMPLE A19

1-(1-cyclohexyl-4-piperidinyl)piperazine-tris-trifluoroacetate

a)1-(1,1-dimethylethoxycarbonyl)-4-[1-(phenylmethyl)-4-peridinyl]piperazine

A solution of 15.0 g (0.8054 mol) of1-(1,1-dimethylethoxycarbonyl)piperazine and 14.26 ml (0.08053 mol) of1-(phenylmethyl)-4-piperidinone in 250 ml of methanol was adjusted to apH of between 5 and 6 by dropwise addition of acetic acid and mixed inbatches with a total of 4.13 g (0.0624 mol) of 95% sodiumcyanoborohydride, whilst taking care to maintain a pH of 5 to 6 byfurther dropwise addition of acetic acid. After stirring for 18 hours atroom temperature the mixture was evaporated down in vacuo, the residuewas made alkaline with soda and divided between water and ethyl acetate.After working up the ethyl acetate phase in the usual way 21.76 g (75.2%of theory) of a highly viscous colourless oil were obtained, R_(f)0.66(FM1).

b) 1-(1,1-dimethylethoxycarbonyl)-4-(4-piperidinyl)piperazine

Prepared analogously to Example A3f) from1-(1,1-dimethylethoxycarbonyl)-4-[1-(phenylmethyl)-4-piperidinyl]piperazineby hydrogenolysis, but using Pearlman's catalyst instead ofpalladium/charcoal, in a yield of 79.7% of theory.

Colourless crystals, R_(f)=0.3 (FM1).

c)1-(1,1-dimethylethoxycarbonyl)-4-(1-cyclohexyl-4-piperidinyl)piperazine

Prepared analogously to Example A19a) from1-(1,1-dimethylethoxycarbonyl)-4-(4-piperidinyl)piperazine andcyclohexanone in a yield of 99% of theory. Colourless, highly viscousoil.

MS: M⁺=251

d) 1-(1-cyclohexyl-4-piperidinyl)piperazine-tris-trifluoroacetate

Prepared analogously to Example A5e) from1-(1,1-dimethylethoxycarbonyl)-4-(1-cyclohexyl-4-piperidinyl)piperazineand trifluoroacetic acid in a quantitative yield. Colourless crystals,R_(f)=0.2 (FM1).

EXAMPLE A20

1-(1-ethyl-4-piperidinyl)piperazine-trihydrochloride

a) 1-(1-ethyl-4-piperidinyl)-4-(phenylmethyl)piperazine

Prepared analogously to Example A19

a) from 1-ethyl-4-piperidinone and 1-(phenylmethyl)piperazine in a yieldof 71% of theory. Colourless, amorphous substance, R_(f)=0.46 (FM4).

b) 1-(1-ethyl-4-piperidinyl)piperazine-trihydrochloride

A mixture of 36.3 g (0.126 mol) of1-(1-ethyl-4-piperidinyl)-4-(phenylmethyl)piperazine, 300 ml of 1Nhydrochloric acid and 200 ml of methanol was hydrogenated at roomtemperature and in the presence of 4.0 g of 10% palladium/charcoal untilthe uptake of hydrogen had ceased. After working up in the usual way22.9 g (59.3% of theory) of a colourless, crystalline substance wasobtained.

MS: M⁺=197

In the same wayexo-1-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)piperazine-trihydrochloridewas obtained fromexo-4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-(phenylmethyl)piperazine(see Example A11a)) by hydrogenolysis in the presence ofpalladium/charcoal in a yield of 91% of theory.

MS: M⁺=209

EXAMPLE A21

1-ethyl-4-(4-piperidinyl)piperidine

a) 1-(phenylmethoxycarbonyl)-4-(4-piperidinyl)piperdine

To a mixture of 72.375 g (0.3 mol) of bipiperidine-dihydrochloride, 1500ml of methanol, 75 ml of water and 100 mg of bromophenol blue were addeddropwise, simultaneously, with stirring and at room temperature, asolution of 51.18 g (0.3 mol) of benzyl chlorocarbonate in 75 ml oftoluene and 6 N sodium hydroxide solution (about 80 ml) were added, sothat the indicator colour changed continuously. After all had beenadded, which took about 4 hours, the mixture was diluted with 300 ml ofwater and the organic solvent was distilled off in vacuo. The aqueousphase remaining was acidified with hydrochloric acid, whilst beingexternally cooled, extracted thoroughly with diethylether and then madealkaline with 50% potassium hydroxide solution. The mixture wasextracted thoroughly with dichloromethane, the combined dichloromethaneextracts were dried over magnesium sulphate and evaporated down invacuo. The colourless, highly viscous, slowly crystallising oilremaining was further processed without any more purification.

Yield: 87.3 g (96.2% of theory).

IR(KEr): 1701.1 cm⁻¹ (C═O)

b) 1-ethyl-4-[1-(phenylmethoxycarbonyl)-4-piperidinyl]piperidine

To a solution of 18.14 g (0.061 mol) of1-(phenylmethoxycarbonyl)-4-(4-piperidinyl)piperidine in 450 ml of amethanol/water mixture (1/1 v/v) were added, with stirring, whilstmaintaining a temperature of 15 to 20° C., 10.05 g (0.152 mol) of 95%sodium cyanoborohydride and 50 mg of bromocresol purple. Then a solutionof 10.57 g (0.24 mol) of acetaldehyde in 50 ml of methanol and 1Nhydrochloric acid were alternately added dropwise so that the colour ofthe mixture changed continuously from blue to yellow. After all had beenadded and the reaction had finished the mixture was adjusted to pH 2with hydrochloric acid and extracted twice with 200 ml of diethylether.The aqueous phase was then made alkaline and extracted thoroughly withdichloromethane. The combined dichloromethane extracts were dried overmagnesium sulphate and evaporated down in vacuo. The colourlesscrystallising residue remaining was purified by column chromatographyover silica gel (30-60 μm) using FM1 as eluant. Yield of colourlesscrystals of melting point 93-96° C.: 7.9 g (39.26 of theory).

IR(KBr): 1699.2 cm⁻¹ (C═O)

c) 1-ethyl-4-(4-piperidinyl)piperidine

A solution of 7.6 g (0.023 mol) of1-ethyl-4-[1-(phenylmethoxycarbonyl)-4-piperidinyl]piperidine in amixture of 70 ml of methanol, 30 ml of water and 10 ml of glacial aceticacid was hydrogenated in the presence of 10% palladium/charcoal at roomtemperature and 3 bar of hydrogen pressure until the uptake of hydrogenhad ceased. After working up in the usual way the desired compound wasobtained as a colourless oil in a quantitative yield.

EXAMPLE A22

Hexahydro-1-methyl-4-(4-piperidinyl)-1H-1,4-diazepline

a)Hexahydro-1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-1H-1,4-diazepine

Prepared analogously to Example A11a) fromhexahydro-1-methyl-1H-1,4-diazepine and 1-(phenylmethyl)-4-piperidinonein a yield of 35% of theory. Colourless viscous oil.

MS: M⁺=287

The following were prepared in the same way:

(1) 1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-piperazine from1-methylpiperazine and 1-(phenylmethyl)-4-piperidinone

Yield: 39.9% of theory, colourless viscous oil

(2) 1-acetyl-4-[1-(phenylmethyl)-4-piperidinyl]piperazine from1-acetylpiperazine and 1-(phenylmethyl)-4-piperidinone

Yield: 24.2% of theory, colourless viscous oil

R_(f): 0.46 (eluant: ethyl acetate/methanol/conc. ammonia 50/50/2 v/v/v)

IR(KBr): 1647 cm⁻¹ (C═O)

MS: M⁺=301

(3) 4-(dimethylamino)-1-[1-(phenylmethyl)-4-piperidinyl]piperidine from4-(dimethylamino)piperidine and 1-(phenylmethyl)-4-piperidinone

Yield: 28.9% of theory; colourless viscous oil

R_(f): 0.58 (eluant: ethyl acetate/methanol/conc. ammonia 50/50/2 v/v/v)

MS: M⁺=301

(4)1-(1,1-dimethylethoxycarbonyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidinefrom 1-(1,1-dimethylethoxycarbonyl)-4-piperidinone and1-(phenylmethyl)piperazine

Yield: 86.6% of theory. Colourless, amorphous substance

R_(f): 0.58 (eluant: dichloromethane/methanol 9/1 v/v)

b) Hexahydro-1-methyl-4-(4-piperidinyl)-1H-1,4-diazepine

Prepared analogously to Example A3f) fromhexahydro-1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-1H-1,4-diazepineby hydrogenolysis but using Pearlman's catalyst instead ofpalladium/charcoal, in a quantitative yield. Colourless viscous oil.

MS: M⁺=197

The following were obtained in the same way:

(1) 1-methyl-4-(4-piperidinyl)piperazine from1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]piperazine in a quantitativeyield. Colourless viscous oil.

MS: M⁺=183

(2) 1-acetyl-4-(4-piperidinyl)piperazine from1-acetyl-4-[1-(phenylmethyl)-4-piperidinyl]piperazine in a yield of81.90 of theory. Colourless crystals.

IR(KBr): 1631 cm⁻¹ (C═O)

(3) 4-(dimethylamino)-1-(4-piperidinyl)piperidine from4-(dimethylamino)-1-[1-(phenylmethyl)-4-piperidinyl]piperidine in ayield of 76.8% of theory. Colourless, amorphous substance.

(4)1-(1,1-dimethylethoxycarbonyl)-4-(1-piperazinyl)piperidine-hydrochloridefrom1-(1,1-dimethylethoxycarbonyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine-hydrochloride.

Yield: 96% of theory. Colourless crystals

R_(f): 0.23 (eluant: dichloromethane/methanol 9/1 v/v)

EXAMPLE A23

4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine-bis-trifluoroacetate

a) 1-(1,1-dimethyethoxycarbonyl)-4-piperidinecarboxylic acid

To a mixture of 25.9 g (0.2 mol) of piperidine-4-carboxylic acid, 200 ml(0.2 mol) of iN sodium hydroxide solution and 200 ml of tetrahydrofuranwere added 48.0 g (0.22 mol) of di-tert.-butyl pyrocarbonate and themixture was stirred overnight at room temperature. The tetrahydrofuranwas distilled off, finally in vacuo, and the remaining aqueous solutionwas acidified with citric acid. The colourless crystals precipitatedwere suction filtered and dried at 40° C. in a circulating air drier.

Yield: 45.5 g (99.2% of theory).

IR(KBr): 1733.9, 1662.5 cm⁻¹ (C═O)

b)1-(1,1-dimethylethoxycarbonyl)-4-[(4-methyl-1-piperazinyl)carbonyl]piperidine

Prepared analogously to Example A15a) from1-(1,1-dimethylethoxycarbonyl)-4-piperidinecarboxylic acid and1-methylpiperazine in the presence of TBTU in a yield of 76% of theory.Colourless, amorphous substance, R_(f)=0.64 (eluant:dichloromethane/methanol/conc. ammonia 50/50/1 v/v/v).

IR(KBr): 1693, 1678 cm⁻¹ (C═O)

The following were prepared in the same way:

(1)1-methyl-4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]1-piperidinefrom 1-methyl-4-piperidinecarboxylic acid and1-(1,1-dimethylethoxycarbonyl)piperazine in a yield of 97% of theory.Colourless crystals.

IR(KBr): 1683.8, 1629.8 cm⁻¹ (C═O)

(2) 1-(1,1-dimethylethoxycarbonyl)-4-(isonicotinoyl)piperazine from1-(1,1-dimethylethoxycarbonyl)-piperazine and 4-pyridinecarboxylic acidin a yield of 76.8% of theory. Colourless crystals of melting point139.2-140.2° C. and R_(f)=0.84 (eluant: dichloromethane/methanol/conc.ammonia 90/10/1 v/v/v).

IR(KBr): 1689.5, 1625.9 cm⁻¹ (C═O)

c) 4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine-bis-trifluoroacetateprepared analogously to Example A5e) from1-(1,1-dimethylethoxycarbonyl)-4-[(4-methyl1-piperazinyl)carbonyl]-piperidineand trifluoroacetic acid in a yield of 89% of theory. Colourless,amorphous substance.

The following were prepared in the same way:

(1) 1-methyl-4-[(1-piperazinyl)carbonyl]-piperidide from1-methyl-4-[[4-(1₁1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-piperidineand trifluoroacetic acid in a yield of 57% of theory. Colourless,amorphous substance.

IR(KBr): 1679.9, 1645.2 cm⁻¹ (C═O)

MS: M⁺=211

(2) 4-(isonicotinoyl)piperazine-trifluoroacetate from1-(1,1-dimethylethoxycarbonyl)-4-(isonicotinoyl)piperazine andtrifluoroacetic acid in a yield of 98.3% of theory. Colourless,amorphous substance.

IR(KBr): 1676.0 cm⁻(C═O)

EXAMPLE 24

Preparation of compounds of the general structure:

Boc-A-NR³R⁴

1-[N²-(1,1-dimethylethoxycarbonyl)-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine

To a mixture of 18.8 g (0.0494 mol) of Boc-Lys(Z)-OH, 6.5 g (0.05 mol)of DIEA, 16 g (0.05 mol) of TBTU, 6.6 g (0.049 mol) of HOBt and 100 mlof dimethylformamide were added dropwise, with stirring, 8.1 g (0.0494mol) of 1-(4-pyridinyl)piperazine, dissolved in 40 ml of DMF, and themixture was stirred overnight at room temperature. The solvent wasremoved in vacuo and the residue was taken up in ethyl acetate. Theethyl acetate phase was then washed three times successively with 70 mlof saturated aqueous sodium hydrogen carbonate solution and once with 70ml of saturated aqueous saline solution, dried over sodium sulphate andevaporated down in vacuo. 24.2 g (93.2% of theory) of a yellowish oilwere obtained, which was used for the following reactions withoutfurther purification.

IR (KBr): 1650, 1713 cm⁻¹ (C═O)

R_(f) (FM1): 0.59

The following were prepared analogously:

A NR³R⁴ Remarks % Yield R_(f) Eluant IR [cm⁻¹] A9 C1 THF as LM 63.2 0.4FM1 (KBr): C═O KHSO₄/ 1705.0; 1649 NaCl soln A4 C1 93.2 0.59 FM1 (KBr):C═O 1647.7; 1712.7 A5 C1 66 0.55 FM1 (KBr): C═O 1655; 1709 A5 C8 54 0.8FM1 (KBr): C═O 1653; 1713 A6 C8 91 0.8 FM1 (KBr): C═O 1645; 1710.8 A10C1 63 0.5 FM1 (KBr): C═O 1665; 1695 A10 C8 30 0.41 FM4 (KBr): C═O 1662;1699

EXAMPLE A25

Preparation of compounds of general formula:

Cbz-A-NR³R⁴

1-[N²-(phenylmethoxycarbonyl)-N⁶-(1,1-dimethyl-ethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine

To a mixture of 100 g (0.263 mol) of Z-Lys(Boc)-OH, 86.1 g (0.268 mol)of TBTU and 36.3 g (0.263 mol) of HOBt in 600 ml of 15 dimethylformamidewere added 43.0 g (0.263 mol) of 1-(4-pyridinyl)-piperazine and 47.2 ml(0.268 mol) of DIEA with stirring and the mixture was stirred overnightat room temperature. The reaction mixture was evaporated down in vacuoand the residue divided between ethyl acetate and aqueous saturatedsodium hydrogen carbonate solution. The aqueous phase was extractedtwice more with a mixture of ethyl acetate/methanol (10/1, v/v) and thecombined organic phases were washed once with saturated sodium hydrogencarbonate solution. The organic phase was, after drying over sodiumsulphate, evaporated down in vacuo and the residue was taken up in 750ml of ethyl acetate and washed four times with 100 ml of water, sixtimes with 100 ml of 1% potassium hydrogen sulphate solution, once with100 ml of water, twice with 100 ml of 3% aqueous ammonia solution andtwice with 100 ml of water. The organic phase was evaporated down afterdrying over sodium sulphate. 120 g (87% of theory) of the desiredproduct were obtained as an oil, which was used without furtherpurification for the subsequent reactions.

IR (KBr): 1709 cm⁻¹ (C═O)

R_(f) (FM1): 0.59

EI-MS: M⁺=525

The following were prepared analogously:

A NR³R⁴ Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] A3 C4 100 A3 C3Triethylamine as 100 0.8 FM1 (KBr): C═O base 1643.3; 1710.8 A11 C1 98.80.5 FM1 (KBr): C═O 1705.0; 1643.3 A3 C1 81 EI: M+ = 525 0.59 FM1 (KBr):C═O 1708.8; A3 C5 LC/SiO₂/FM4 95 YED: M = 525 0.67 FM4 A3 C6THF,LC/SiO₂/FM4 92 0.82 FM4 (KBr): C═O 1710.8; 1641.3 A3 C8 Furtherreacted as 100 crude product

EXAMPLE A26

Preparation of compounds of general formula:

H-A-NR³R⁴

1-[N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine

To a mixture of 24.2 g (46 mmol) of1-[N²-(1,1-dimethylethoxycarbonyl)-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazineand 150 ml of methylene chloride were added 50 ml of trifluoroaceticacid and the reaction mixture was stirred overnight at room temperature.The reaction mixture was neutralised by the addition of saturatedaqueous sodium hydrogen carbonate solution, the organic phase was driedand evaporated down in vacuo. 12 g (62% of theory) of the desiredcompound were obtained as a colourless oil.

IR (KBr): 1648 cm⁻¹ (C═O)

R_(f) (FM1): 0.5

The following were prepared analogously:

% A NR³R⁴ Remarks Yield R_(f) Eluant IR [cm⁻¹] A9 C1 100 0.4 FM2 (KBr):C═O 1676.0; 1645.2 A4 C1 61.5 0.48 FM1 (KBr): C═O 1647.7; 1712.7 A5 C155 0.42 FM1 (KBr): C═O 1651 A5 C8 further reacted 100 0.19 FM1 as crudeproduct A6 C1 82 0.3 FM1 (KBr): C═O 1647; 1676 A6 C8 further reacted 1000.23 FM1 (KBr): C═O as crude 1674 product A10 C1 38 0.55 FM1 (KBr): C═O1643 A10 C8 further reacted 100 0.15 FM1 as crude product

EXAMPLE A27

Preparation of compounds of general formula:

H-A-NR³R⁴

1-[N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine

A solution of 120 g (0.228 mol) of1-[N²-(phenylmethoxycarbonyl)-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazinein 1000 ml of methanol and 240 ml of 1M aqueous potassium hydrogensulphate solution was hydrogenated in the presence of 30 g palladium oncharcoal (100) at 20° C. and 3 bar of hydrogen pressure until the uptakeof hydrogen had ceased. The catalyst was filtered off, the filtrateevaporated down in vacuo, the residue was taken up inisopropanol/methanol and adjusted to pH 7-8 by the addition of aconcentrated aqueous ammonia solution. The solution was filtered andevaporated to dryness. 87 g (97% of theory) of an oil were obtained.

IR (KBr): 1634, 1701 cm⁻¹ (C═O)

R_(f): 0.79 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v)

The following were prepared analogously:

A NR³R⁴ Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] A3 C4 93 ESI: M + H =391 0.6 FM1 (KBr): C═O (M + Na = 413) 1637.5; 1706.9 A3 C3 100 0.3 FM1(KBr): C═O 1641.3; 1705 A11 C1 78.5 0.2 FM1 (KBr): C═O 1701.1; 1641.3 A7C1 without KHSO₄ 80.2 0.2 FM7 A3 C1 97 0.79 ethyl (KBr): C═Oacetate/methanol/ 1633.6; 1701.1 conc. aqueous ammonia 6/4/1 (v/v/v) A3C5 without KHSO₄ 53 0.39 FM4 (KBr): C═O 1733.9; 1624.0 A3 C6 withoutKHSO₄ 89 0.38 FM4 (KBr): C═O 1706.9; 1645.2 A3 C8 further reacted as 1000.3 FM1 crude product

EXAMPLE A28

Preparation of compounds of general formula:

1-[N²-[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

To a mixture of 2.58 g (5.88 mmol) ofN-[(1,1-dimethylethoxy)-carbonyl]-3,5-dibromo-D-tyrosine, 1.03 g (8mmol) of DIEA, 1.93 g (6 mmol) of TBTU, 0.79 g (5.8 mmol) of HOBt and100 ml of dimethylformamide were added dropwise, 2.5 g (5.88 mmol) of1-[N6-[(phenylmethoxy)-carbonyl]-L-lysyl]-4-(4-pyridinyl)piperazine,dissolved in 50 ml of dimethylformamide, with stirring. The reactionmixture was stirred overnight at room temperature, then evaporated downin vacuo and the residue was taken up in ethyl acetate. The organicphase was washed twice with aqueous saturated sodium hydrogen carbonatesolution and once with aqueous saturated saline solution, dried andevaporated down in vacuo. The purification was carried out by columnchromatography (aluminium oxide, activity stage III (6% water content)(ICN Biomedicals), eluant: ethyl acetate/methanol/ammonia=8/2/0.5(v/v/v), followed by methanol/ammonia =7/3 (v/v)). 4.0 g (80% of theory)of an amorphous substance were obtained.

IR (KBr): 1643, 1709 cm⁻¹ (C═O)

R_(f): 0.52(FM1)

ESI-MS: (M+H)⁺=845/847/849 (Br₂)

The following were prepared analogously (in each case n=1)

R² A NR³R⁴ Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] AS7 A0 C4 LM: THF;100 reacted as crude product AS1 A0 C11 reacted as 69 crude product AS4A0 C20 59 ESI: (M + H)⁺ = (KBr): C═O 600/2/4 (Br₂) 1639; 1707 AS1 A0 C471 AS4 A0 C11 53 0.5 FM1 AS7 A0 C1 reacted as 100 (KBr): C═O crudeproduct 1644 AS4 A7 C1 NEt₃ as base; 100 0.4 FM8 reacted as crudeproduct AS1 A4 C1 80 ESI: (M + H)⁺ = 0.52 FM1 (KBr): C═O 845/7/9 (Br₂)1643.3; 1708.8 AS4 A0 C5 Boc-AS4 83 EI: M⁺ = 0.69 FM5 (KBr): C═OLC/SiO₂/FM5 581/3/5 (Br₂) 1706.9; 1641.3 AS4 A0 C15 LC/SiO₂/FM4 86 EI:M⁺ = 0.83 FM4 (KBr): C═O 382/4/6 (Br₂) 1706.9; 1641.3 AS1 A0 C5LC/SiO₂/FM5 81 0.5 FM5 (KBr): C═O 1705.0; 1637.5 AS4 A0 C16 LC/SiO₂/FM485 EI: (M + H)⁺ = 0.42 FM4 (KBr): C═O THF 582/4/6 (Br₂) 1706.9; 1643.3AS1 A0 C15 THF 76 0.53 FM4 (KBr): C═O LC/SiO₂/FM4 1701.1; 1637.5 AS4 A0C3 LC/SiO₂/FM6 83 ESI: (M + H)⁺ = 0.71 FM6 (KBr): C═O 598/600/2 (Br₂)1706.9; 1641.3 AS1 A0 C16 LC/SiO₂/FM4 85 0.35 FM1 (KBr): C═O 1705;1641.3 AS1 A0 C6 LC/SiO₂/FM6 84 0.54 FM6 (KBr): C═O 1701.1; 1635.5 AS4A0 C18 LC/SiO₂/FM4 95 0.66 FM4 (KBr): C═O 1705; 1641.3 AS1 A0 C37 900.43 FM1 (KBr): C═O 1645; 1714.5 AS4 A0 C37 95 0.51 FM4 (KBr): C═O1643.3; 1705 AS4 A0 C22 75 (KBr): C═O 1635.5; 1708.8 AS4 A0 C21 92 M⁺ =0.42 FM4 (KBr): C═O 582/4/6 (Br₂) 1643; 1705 AS4 A5 C1 69 ESI: (M + H)⁺= (KBr): C═O 939/41/43 (Br₂) 1653; 1709 AS4 A0 C23 85 (KBr): C═O 1645;1709 AS4 A10 C1 65 M⁺: 652/4/6 (KBr):C═O 1649; 1707 AS4 A0 C24 79 M⁺:589/91/93 (KBr): C═O 1643; 1707 AS4 A5 C8 76 (KBr): C═O 1643; 1713 AS4A6 C1 95 (KBr): C═O 1645; 1710.8 AS4 A6 C8 88 M⁺: 657/9/61 (KBr): C═O1628; 1713 AS4 A10 C8 46 ESI: (M + H)⁺ = (KBr): C═O 858/60/62 (Br₂)1647; 1707 AS4 A0 C26 46 (KBr): C═O 1637.5; 1707 AS1 A0 C1 furtherreacted as 100 crude product AS1 A0 C8 55 0.3 dichloromethane/ (KBr):C═O methanol 9/1 1632 AS1 A0 C18 84 ESI: (M + H)⁺ = 0.4 FM4 (KBr): C═O613/5/7 (Br₂) 1641; 1707 AS1 A0 C3 81 (KBr): C═O 1638; 1701 AS1 A0 C2170 0.28 FM4 (KBr): C═O 1643; 1707 AS4 A0 C6 47 (KBr): C═O 1639; 1707 AS4A0 C19 90 (KBr): C═O 1639; 1707 AS9 A0 C1 further reacted as 47 crudeproduct AS1 A7 C1 NEt₃ as base; 83 0.28 FM1 further reacted as crudeproduct AS4 A0 C38 67 0.5 FM1 AS4 A0 C37 84 AS4 A0 C39 100 0.68 FM1(raw) AS4 A0 C40 36 AS1 A0 C42 90 0.43 FM1 (KBr): C═O 1645/1715 AS4 A0C42 100 0.51 FM4 (KBr): C═O 1643/1705 AS1 A0 C43 78 0.9 EE/MeOH (KBr):C═O 95/5 1636/1676/1659 AS1 A0 C44 47 0.9 EE/MeOH (KBr): C═O 95/51638/1701 AS1 A0 C45 72 EI: M⁺ = 0.9 EE/MeOH (KBr): C═O 591/3/5 (Br₂)9/1 1638/1695 AS1 A0 C47 80 EI: M⁺ = 0.95 EE/MeOH (KBr): C═O 596/98/600(Br₂) 9/1 1636/1705 AS1 A0 C49 89 0.9 EE/MeOH (KBr): C═O 9/1 1636/1684AS4 A0 C44 69 0.9 EE/MeOH (KBr): C═O 9/1 1643/1707; CN 2235 AS1 A0 C5093 EI: M⁺ = 0.9 EE/MeOH (KBr): C═O 598/600/602 (Br₂) 9/1 1636/1705 AS1A0 C51 100 0.1 EE/MeOH/ (KBr): C═O NH₄OH 5/5/0.1 1638/1707 AS4 A0 C52 630.56 FM1 (KBr): C═O 1641/1705 AS4 A0 C53 83 EI: M⁺ = (KBr): C═O 601/3/5(Br₂) 1638/1705 AS4 A0 C64 41 ESI: (M + H)⁺ = (KBr): C═O 610/12/14 (Br₂)1639/1701 AS1 A0 C53 66 0.45 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 70/30/11639/1709 AS4 A0 C51 88 0.35 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 50/50/0.51641/1691 AS4 A0 C66 77 EI: M⁺ = 0.75 CH₂Cl₂/MeOH/ (KBr): C═O 629/31/33(Br₂) NH₄OH 9/1/0.1 1641/1707 AS16 A0 C8 100 0.8 FM1 AS16 A0 C1 56 0.5EE/MeOH/ (KBr): C═O NH₄OH 9/1/1 1695 AS4 A0 C8 100 AS1 A0 C53 70.0 EI:M⁺ = 0.10 CH₂Cl₂/MeOH/ (KBr): C═O 502/4/6 (Br₂) NH4OH 70/30/1 1676 AS4A0 C70 47.0 (KBr): C═O 1645/1707 AS1 A0 C64 31.0 0.50 CH₂Cl₂/MeOH/(KBr): C═O NH4OH 90/10/1 1639/1707 AS1 A0 C70 20.0 AS4 A0 C72 50.0 0.50CH₂Cl₂/MeOH/ NH4OH 90/10/1 AS19 A0 C8 98.0 AS35 A0 C8 92.0 0.70 FM1 AS36A0 C8 65.0

EXAMPLE A29

Preparation of compounds of general formula:

1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyridinyl)piperazine

A mixture of 39 g (0.089 mol) of4-amino-3,5-dibromo-N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanine,35.7 g (0.111 mol) of TBTU, 12.3 g (0.089 mol) of HOBt, 14.5 g (0.089mol) of 1-(4-pyridinyl)-piperazine and 19.6 ml of (0.111 mol) of DIEA in1000 ml of tetrahydrofuran was stirred overnight at room temperature.The reaction mixture was extracted once with saturated aqueous salinesolution and twice with saturated aqueous sodium hydrogen carbonatesolution. The combined aqueous phases were extracted once withtetrahydrofuran and the combined tetrahydrofuran phases were washed oncewith saturated aqueous saline solution. After drying the organic phasewith sodium sulphate it was evaporated down in vacuo and the residue wastaken up in ethyl acetate. The ethyl acetate phase was filtered afterdrying again and evaporated down in vacuo. 52.5 g of the intermediatecompound were obtained as a viscous oil, which was then mixed with 300ml of methylene chloride and 80 ml of trifluoroacetic acid and stirredovernight at room temperature. The reaction mixture was evaporated downin vacuo, the residue formed was triturated with ether. 45.8 g (72% oftheory) of the desired product were obtained as a white amorphous solid.

IR (KBr): 1643, 1674 cm⁻¹ (C═O)

R_(f): 0.36 (ethyl acetate/methanol =6/4 (v/v))

The following were prepared analogously (in each case n=1)

R² A NR³R⁴ Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] AS7 A0 C8 Crudeproduct; 84 Boc-cleaving with pure TFA AS4 A0 C8 63 ESI: (M + H)⁺ =(KBr): C═O 486/88/90 (Br₂) 1632 AS4 A0 C4 63 ESI: (M + H)⁺ = (KBr): C═O481/3/5 (Br₂) 1620 AS1 A9 C1 55 0.25 FM2 (KBr): C═O 1674.1; 1643.3 AS4A0 C8 81 ESI: (M + H)⁺ = 0.6 FM2 (KBr): C═O 486/8/90 (Br₂) 1629.8 AS4 A0C1 72 0.38 ethyl acetate/ (KBr): C═O methanol = 6/4 (v/v) 1643.3; 1674.1AS1 A0 C20 30 AS4 A0 C65 41 EI: M⁺ = (KBr): C═O 515/17/19 (Br₂) 1618 AS1A0 C65 15 ESI: (M + H)⁺ = 0.08 FM1 (KBr): C═O 517/19/21 (Br₂) 1635 AS4A0 C78 77.0 ESI: (M + H)⁺ = 0.30 CH₂Cl₂/MeOH/ (KBr): C═O 529/31/33 (Br₂)NH4OH = 90/10/1 1674 AS1 A0 C78 60.0 ESI: (M + H)⁺ = 0.10 CH₂Cl₂/MeOH/(KBr): C═O 531/33/35 (Br₂) NH₄OH = 80/20/1 1670 AS4 A0 C71 43.0 0.20CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH = 90/10/1 1678 AS31 A0 C20 39.0 EI: M⁺ =382 0.30 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH = 80/20/1 1678 AS31 A0 C53 83.0EI: M⁺ = 383 (KBr): C═O 1678

EXAMPLE A30

Preparation of compounds of general formula:

1-[N²-[N-(9-fluorenylmethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine

A mixture of 63 g (0.1123 mol) ofN-[(9-fluorenylmethoxy)carbonyl]-3,5-dibromo-D-tyrosine, 44 g (0.1123mol) of1-[N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine,39.7 g (0.1235 mol) of TBTU, 15.5 g (0.1123 mol) of HOBt, 21.7 ml(0.1235 mol) of DIEA and 600 ml of dimethylformamide was stirred for 20hours at room temperature. The reaction mixture was evaporated down invacuo and the residue divided between ethyl acetate/methanol (10/1 v/v)and saturated aqueous sodium hydrogen carbonate solution. The organicphase was washed once with saturated aqueous sodium hydrogen carbonatesolution and after drying evaporated down in vacuo. The residue wasrecrystallised twice from isopropanol (22.6g; 22% of theory), the motherliquors were combined, evaporated down and purified by columnchromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM;eluant: ethyl acetate/methanol=8/2 (v/v)). A further 28.0 g (26.7% oftheory)of the desired end product were obtained. Total yield: 49% oftheory.

IR (KBr): 1641, 1705 cm⁻¹ (C═O)

R_(f): 0.46 (ethyl acetate/methanol =6/4 (v/v))

ESI-MS: (M+H)⁺=933/935/937 (Br₂)

The following were prepared analogously:

R² A NR³R⁴ Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] AS1 A3 C1 48 ESI:(M + H)⁺ = 0.46 Ethyl acetate/ (KBr): C═O 933/5/7 (Br₂) methanol = 6/4(v/v) 1641.3; 1705.5 AS1 A3 C5 THF/SiO₂/FM4 80 ESI: (M + H)⁺ = 0.72 FM1(KBr): C═O 933/5/7 (Br₂) 1701.1; 1635.5 AS1 A3 C6 THF 60 ESI: M⁻ = 0.47FM4 (KBr): C═O 960/2/4 (Br₂) 1712.7; 1631.7 AS5 A3 C1 THF 61 ESI: (M +H)⁺ = 0.36 FM4 (KBr): C═O LC/SiO₂/FM4 917/19/21 (Br₂) 1708.8; 1645.2Diastereomers AS10 A0 C1 THF 90 0.52 FM4 AS1 A3 C18 73 0.46 FM1 (KBr):C═O 1635.5; 1712.7 AS10 A3 C1 THF 85 (KBr): C═O 1643.3; 1708.8 AS10 A3C4 THF 82 (KBr): C═O 1639.4; 1710.8 AS10 A3 C1 THF 85 (KBr): C═O 1643;1709 AS4 A3 C18 94 ESI: (M + H)⁺ = (KBr): C═O 963/5/7 (Br₂) 1633.6; 1711AS15 A0 C8 90 (KBr): C═O 1635.5; 1617.5 AS12 A0 C8 44 ESI: (M + H)⁺ =(KBr): C═O 577 1630; 1714.6 AS10 A0 C4 88 0.49 FM4 (KBr): C═O 1635.5;1716.5 AS1 A3 C1 70 0.7 FM7

EXAMPLE A31

Preparation of compounds of general formula:

1-[N²-(3,5-dibromo-D-tyrosyl)-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

To a mixture of 63 g (0.1123 mol) ofN-[(9-fluorenylmethoxy)carbonyl]-3,5-dibromo-D-tyrosine, 44 g (0.1123mol) of1-[N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine,39.7 g (0.1235 mol) of TBTU, 15.5 g (0.1123 mol) of HOBt and 1500 ml oftetrahydrofuran were slowly added dropwise 21.7 ml (0.1235 mol) of DIEAand the reaction mixture was then stirred for 2 hours at roomtemperature. After the addition of 200 ml of diethylamine the mixturewas again stirred overnight at room temperature. The reaction mixturewas mixed with 1000 ml of saturated saline solution, stirred thoroughlyand the aqueous phase was separated off. After extracting the aqueousphase three times with 500 ml of tetrahydrofuran and combining theorganic phases the mixture was washed three times with 500 ml ofsaturated aqueous saline solution, three times with 200 ml of saturatedaqueous sodium hydrogen carbonate solution and once with 500 ml ofsaturated aqueous saline solution. The organic phase was dried and thenevaporated down in vacuo. The residue was purified by columnchromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM,eluant: ethyl acetate/methanol/conc. aqueous ammonia=8/1/0.25 (v/v/v)).40.0 g (50% of theory)of the desired end product were obtained.

IR (KBr): 1641, 1699 cm⁻¹ (C═O)

R_(f): 0.2 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v))

ESI-MS: (M+H)⁺=711/713/715 (Br₂)

The following were prepared analogously (in each case n=1)

R² A NR³R⁴ Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] AS4 A3 C8 crude 43AS4 A3 C1 crude 100 0.4 FM1 AS4 A3 C4 79 ESI: (M + H)⁺ = 0.7 FM7 (KBr):C═O 709/11/13 (Br₂) 1637.5; 1705 AS4 A0 C69 82 ESI: (M + H)⁺ = (KBr):C═O 587/9/81 (Br₂) 1618/1645/1690 AS4 A0 C46 38 0.55 CH₂Cl₂/MeOH/ (KBr):C═O NH₄OH 90/10/1 1614/1639 AS4 A0 C48 54 EI: M⁺ = 0.52 CH₂Cl₂/MeOH/(KBr): C═O 522/4/6 (Br₂) NH₄OH 90/10/2 1638 AS11 A0 C53 71.0 EI: M⁺ =469 0.20 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 90/10/1 1637/1732 AS11 A0 C2045.0 EI: M⁺ = 468 0.40 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 90/10/1 1635/1732AS31 A0 C72 100.0 EI: M⁺ = 411 0.45 FM1 (KBr): C═O 1664 AS11 A0 C72 33.0EI: M⁺ = 497 0.30 FM1 (KBr): C═O 1630/1641

EXAMPLE A32

Preparation of compounds of general formula:

1-[N²-(3,5-dibromo-D-tyrosyl)-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

To a mixture of 4 g (4.7 mmol) of1-[N²-[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazineand 80 ml of methylene chloride were added 20 ml of trifluoroacetic acidand the reaction mixture was stirred overnight at room temperature. Thereaction mixture was neutralised by the addition of saturated aqueoussodium hydrogen carbonate solution, the organic phase was dried oversodium sulphate and evaporated down in vacuo. 2.2 g (64% of theory) ofan amorphous solid were obtained.

IR (KBr): 1643, 1680 cm⁻¹ (C═O)

R_(f): 0.5 (FM1)

ESI-MS: (M+H)⁺=745/747/749 (Br₂)

The following were prepared analogously (in each case n=1)

R² A NR³R⁴ Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] Mp. (° C.) AS7 A0C4 crude product; 51 0.30 FM1 pure TFA AS1 A0 C11 95 ESI: (M + H)⁺ =(KBr): C═O 503/5/7 (Br₂) 1676 AS4 A0 C20 100 ESI: (M + H)⁺ = 500/2/4(Br₂) AS1 A0 C4 100 ESI: (M + H)⁺ = (KBr): C═O 481/3/5 (Br₂) 1678 AS4 A0C11 74 AS7 A0 C1 reacted as 100 crude product AS4 A7 C1 reacted as 1000.40 EE/MeOH crude product 7/3 v/v AS1 A4 C1 64 ESI: (M + H)⁺ = 0.50 FM1(KBr): C═O 745/7/9 (Br₂) 1643.3; 1679.9 AS4 A0 C5 89 0.32 FM4 (KBr): C═O1637.5 AS4 A0 C15 93 0.33 FM4 (KBr): C═O 1618.2 AS1 A0 C5 89 0.25 FM4(KBr): C═O 154-157 1639.4 AS4 A0 C16 LC/SiO₂/FM4 90 0.30 FM4 (KBr): C═O1635.5 AS1 A0 C15 89 0.20 FM4 (KBr): C═O 160-164 1639.4 AS4 A0 C3LC/SiO₂/FM4 98 0.37 FM4 (KBr): C═O 1683.8; AS4 A0 C6 89 0.28 FM4 (KBr):C═O 1637.5 AS1 A0 C16 95 0.57 FM1 (KBr): C═O 1683.8 AS1 A0 C6LC/SiO₂/FM4 56 EI: M⁺ = 0.24 FM4 (KBr): C═O 511/3/5 (Br₂) 1637.5 AS4 A0C18 90 EI: M⁺ = 0.50 FM1 (KBr): C═O 512/4/6 (Br₂) 1624.0 AS4 A0 C37 930.24 FM4 (KBr): C═O 1635.5; 1684 AS4 A0 C22 88 M⁺ = (KBr): C═O 502/4/6(Br₂) 1618.2 AS4 A0 C21 52 M⁺ = 0.55 FM1 (KBr): C═O 482/4/6 (Br₂) 1681.8AS1 A0 C37 89 0.32 FM1 (KBr): C═O 1681.8 AS4 A5 C1 crude (KBr): C═O1645; 1676 AS4 A0 C23 88 (KBr): C═O 1643 AS4 A10 C1 47 ESI: (M + H)⁺ =(KBr): C═O 553/5/7 (Br₂) 1653 AS4 A5 C8 67 M⁺ = (KBr): C═O 543/5/7 1645AS4 A6 C1 59 (KBr): C═O 1643 AS4 A0 C24 94 M⁺ = (KBr): C═O 489/91/931618; 1637.5 AS4 A6 C8 70 (KBr): C═O 1639.4 AS4 A10 C8 82 M⁺ = (KBr):C═O 557/9/61 1651 AS4 A0 C26 88 (KBr): C═O 1626 AS1 A0 C1 96 ESI: (M +H)⁺ = 0.18 FM1 (KBr): C═O 483/5/7 (Br₂) 1680 AS1 A0 C8 crude 69 AS1 A0C18 82 0.27 FM1 (KBr): C═O 1684 AS1 A0 C3 100 0.38 FM1 (KBr): C═O 1682AS1 A0 C21 89 0.26 FM1 (KBr): C═O 1595; 1615 AS4 A0 C3 99 0.37 FM4(KBr): C═O 1618; 1636; 1683 AS4 A0 C19 98 ESI: (M + H)⁺ = 0.47 FM4(KBr): C═O 498/500/502 (Br₂) 1638; 1682 AS9 A0 C1 Crude product 96 AS1A7 C1 37 0.42 FM7 AS4 A0 C38 80 0.25 FM1 AS4 A0 C37 86 AS4 A0 C39 73 AS4A0 C40 92 EI: M⁺ = (KBr): C═O 515/7/9 1674 AS1 A0 C42 100 0.32 FM1(KBr): C═O crude 1682 AS4 A0 C42 95 0.24 FM4 (KBr): C═O 1636/1684 AS1 A0C43 66 0.1 FM7 (KBr): C═O 1659 AS1 A0 C44 59 0.15 CH₂Cl₂/MeOH/ (KBr):C═O NH₄OH 90/10/1 1676 AS1 A0 C45 82 ESI: (M + H)⁺ = 0.10 EE/MeOH 9/1(KBr): C═O 492/4/6 (Br₂) 1678 AS1 A0 C47 89 0.52 FM7 (KBr): C═O1634/1666 AS1 A0 C49 84 0.15 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 1678 AS4 A0C44 93 EI: M⁺ = 0.45 EE/MeOH 9/1 (KBr): C═O 504/6/8 (Br₂) 1653; CN 2239AS1 A0 C50 100 EI: M⁺ = 0.10 EE/MeOH 9/1 (KBr): C═O 498/500/502 (Br₂)1636 AS1 A0 C51 100 EI: M⁺ = 0.05 EE/MeOH/ (KBr): C═O 530/2/4 (Br₂)NH4OH 5/5/0.1 1678 AS4 A0 C52 97 0.15 FM1 (KBr): C═O 1620/1688 AS4 A0C53 58 ESI: (M + H)⁺ = 0.05 EE/MeOH/ (KBr): C═O 502/4/6 (Br₂) NH₄OH5/5/0.1 1678 AS4 A0 C64 100 (KBr): C═O 1647/1678 AS1 A0 C53 70 EI: M⁺ =0.15 CH₂Cl₂/MeOH/ (KBr): C═O 502/4/6 (Br₂) NH₄OH 70/30/1 1676 AS4 A0 C51100 0.05 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 1680 AS4 A0 C66 100 0.27CH₂Cl₂/MeOH/ NH₄OH AS16 A0 C8 76 0.40 FM1 AS16 A0 C1 28 0.20 EE/MeOH/NH₄OH 9/1/1 AS4 A0 C70 96 0.20 EE/MeOH/ (KBr): C═O NH₄OH 80/20/10.5 1676AS1 A0 C64 100 EI: M⁺ = (KBr): C═O 510/1214 1674 AS1 A0 C70 100 (KBr):C═O 1674 AS4 A0 C72 100 ESI: (M + H)⁺ = 0.10 CH₂Cl₂/MeOH/ (KBr): C═O530/2/4 (Br₂) NH₄OH 80/20/1 1678 AS19 A0 C8 100 AS35 A0 C8 72 0.60 FM1AS36 A0 C8 80 0.52 FM1 (KBr): C═O 1674

EXAMPLE A33

4-(4-pyridinyl)-1-[3-(4-pyridinyl)-D,L-alanyl]-piperazine-hydrochloride

16.4 g (0.04 mol) of1-[N-[(1,1-dimethylethoxy)carbonyl]-3-(4-pyridinyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine,dissolved in 100 ml of methanol, were mixed with 20 ml of etherealhydrochloric acid and the reaction mixture was heated to 40° C. Thedesired compound crystallised out of the reaction mixture.

yield: 9.2 g (60% of theory)

R_(f): 0.1 (FM1)

Mp.: 198-200° C.

EXAMPLE A34

Preparation of compounds of general formula:

1-[N²-(3,5-dibromo-D-tyrosyl)-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

A mixture of 50 g (53.5 mmol) of1-[N²-[N-(9-fluorenylmethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazineand 300 ml of diethylamine was heated to 60° C. with stirring. 100 ml ofmethanol were added and stirring was continued for a further 5 hours at60° C. The reaction mixture was evaporated down in vacuo and the residuewas purified by column chromatography (MN-silica gel 60, Macherey-Nagel,70-230 mesh ASTM, eluant: ethyl acetate/methanol=6/4 (v/v)). 26 g (68%of theory) of a white foam were obtained.

IR (KBr): 1641, 1691 cm⁻¹ (C═O)

R_(f): 0.2 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v))

ESI-MS: (M+H)⁺=710/712/714 (Br₂)

The following were prepared analogously:

R² A NR³R⁴ n Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] AS1 A3 C4 1 85ESI: M + H = 0.2 FM1 (KBr): C═O 710/2/4 (Br₂) 1635.5; 1695.3 AS1 A3 C8 198 (KBr): C═O 1635; 1705 AS1 A3 C1 1 68 EI: M⁺ = 0.2 ethyl acetate/(KBr): C═O 710/2/4 (Br₂) methanol/NH₄OH = 1641.3; 1691.5 6/4/1 (v/v/v)AS1 A3 C5 1 THF as solvent; purified by 56 ESI: M + H = 0.3 FM1(KBR):C═O column chromatography: 711/3/5 (Br₂) 1695.3; 1635.5 silicagel/FM1 AS1 A3 C6 1 THF as solvent; purified by 90 EI: M⁺ = 0.49 FM1(KBr): C═O column chromatography: 739/41/43 (Br₂) 1695.3; 1629.8 silicagel/FM1 AS5 A3 C1 1 THF as solvent; purified by 93 0.25/ FM4 (KBr): C═Ocolumn chromatography: 0.37 1705.0; 1643.3 silica gel/FM4; diastereomersAS10 A0 C1 1 71 0.5 FM1 (KBr): C═O 1641.3 AS1 A3 C18 1 94 (KBr): C═O1647; 1722.5 AS10 A3 C1 1 49 M⁺ = (KBr): C═O 694/6/8 (Br₂) 1643; 1703AS10 A3 C4 1 46 ESI: M + H = (KBr): C═O 694/6/8 (Br₂) 1639.4; 1705 AS10A3 C4 1 46 ESI: M + H = (KBr): C═O 694/6/8 (Br₂) 1639.4; 1705 AS10 A3 C11 49 M⁺ = (KBr): C═O 694/68/70 (Br₂) 1643; 1703 AS4 A3 C18 1 46 ESI: M +H = (KBr):C═O 741/3/5 (Br₂) 1641.3; 1705 AS15 A0 C8 1 100 M⁺: 321 (KBr):C═O 1637.5 AS12 A0 C8 1 81 (KBr): C═O 1630 AS10 A0 C4 1 THF as solvent68 0.38 FM4 (KBr): C═O 1635.5 AS1 A3 C1 0 crude product 100 0.3 FM7

EXAMPLE A35

1-[N²-[N-[[[2-(2-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinl)-piperazine

To a solution of 1.0 g (1.34 mmol) of1-[N²-(-3,5-dibromo-D-tyrosyl)-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazinein 80 ml of tetrahydrofuran were added 0.28 g (1.6 mmol) of2-methoxyphenethyl isocyanate and the mixture was stirred for 3 days atroom temperature. The reaction mixture was evaporated down in vacuo andthe residue was purified by column chromatography (MN-silica gel 60,Macherey-Nagel, 70-230 mesh ASTM, eluant: methylenechloride/methanol/cyclohexane/ammonia=350/75/75/10 (v/v/v/v)). 0.5 g(40% of theory) of a colourless amorphous solid was obtained.

IR(KBr): 1639 cm⁻¹ (C═O)

R_(f): 0.49 (FM1)

ESI-MS: (M+H)⁺=922/924/926 (Br₂)

EXAMPLE A36

Preparation of compounds of general formula:

methyl4-amino-3,5-dibromo-N²-[[(2-phenylethyl)amino]carbonyl]-D-phenylalanine

A mixture of 1.27 g (7.73 mmol) of CDT in 150 ml of tetrahydrofuran wasmixed, whilst cooling with ice, with 0.72 ml (5.15 mmol) oftriethylamine and 2.0 g (5.15 mmol) ofmethyl-4-amino-3,5-dibromo-D-phenylalanine-hydrochloride, stirred for afurther 30 minutes whilst cooling with ice and stirred for 1 hour atroom temperature. Then 0.82 ml (6.44 mmol) of benzene ethanamine wereadded and the mixture was refluxed for 5 hours. The reaction mixture wasevaporated down in vacuo, the residue was taken up in ethyl acetate andwashed with saturated aqueous sodium hydrogen carbonate solution. Afterdrying the organic phase the solvent was removed in vacuo, the residuewas stirred with ether and the precipitate was filtered off. 1.69 g (66%of theory) of an amorphous solid were obtained.

IR(KBr): 1632, 1732 cm⁻¹ (C═O)

R_(f): 0.63 (ethyl acetate)

ESI-MS: (M+H)⁺=498/500/502 (Br₂)

The following were prepared in the same way (in each case n=1):

RCO R² Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] N6 AS1 further reacted100 0.60 FM1 as crude product N15 AS6 DMF/THF = 1/1 100 ESI: (M + H)⁺ =0.65 FM1 (KBr): C═O (v/v) as solvent 517/9 (Br) 1745.5; 1676.0 N2 AS1 990.53 FM1 (KBr): C═O 1716.5 N8 AS4 66 ESI: (M + H)⁺ = 0.63 ethyl acetate(KBr): C═O 498/500/502 (Br₂) 1631.7; 1732.0 N15 AS4 92 0.85 ethylacetate/ (KBr): C═O methanol = 8/2 (v/v) 1620.1; 1737.8 N23 AS4 95 EI:M⁺ = 0.86 ethyl acetate/ (KBr): C═O 572/4/6/8 (Br₂.Cl) methanol = 8/2(v/v) 1732.0; 1641.3 N2 AS2 100 EI: M⁺ =406 0.86 FM1 (KBr):C═O 1629.8;1722.3; 1741.6 N15 AS1 DIEA 47 0.75 FM1 N15 AS3 38 0.60 t.-butyl- (KBr):C═O methylether/ 1695.5 petroleum ether = 9/1 (v/v) N66 AS21 76 0.60 EE(KBr): C═O 1662/1734 N66 AS1 100 N66 AS4 63 0.56 FM1 N122 AS1 95 N122AS4 88 N66 AS17 22 ESI: (M + H)⁺ = 0.25 FM1 (KBr): C═O 623/5/7 (Br₂)1663/1740 N66 AS18 65 0.53 EE N66 AS19 79 0.50 FM1 (KBr): C═O 1663/1734N66 AS5 90 ESI: (M + H)⁺ = 0.78 FM1 (KBr): C═O 607/09/11 (Br₂)1637/1663/1740 N66 AS22 68 0.74 FM1 N66 AS23 100 (KBr): C═O 1738/1662N66 AS25 100 ESI: (M + H)⁺ = 0.52 FM1 472 N66 AS49 100 0.80 FM1

EXAMPLE A37

Preparation of compounds of general formula:

4-amino-3,5-dibromo-N²-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanine

To a solution of 2.8 g (4.9 mmol) of methyl4-amino-3,5-dibromo-N²-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalaninein a mixture of 30 ml of methanol and 20 ml of water were added 0.25 g(10.0 mmol) of lithium hydroxide and the mixture was then stirred for 3hours at room temperature. After the addition of 2.0 g (50 mmol) ofsodium hydroxide the mixture was diluted with 50 ml of water. Thereaction mixture was stirred for 15 minutes in an ultrasound bath, thenstirred overnight at room temperature and evaporated down in vacuo. Theresidue was mixed with 100 ml of water and the aqueous phase wasextracted twice with 50 ml of ether. By the addition of 2 M aqueoushydrochloric acid the aqueous phase was adjusted to a pH of 3-4 andextracted three times with ethyl acetate. The combined ethyl acetatephases were washed once with water, then dried and evaporated down invacuo. 1.6 g (58% of theory) of a yellowish-brown oil were obtained.

IR(KBr): 1616, 1724 cm⁻¹ (C═O)

R_(f): 0.33 (ethyl acetate/methanol=8/2 (v/v))

ESI-MS: (M+H)⁺=557/559/561/563 (Br₂, Cl)

The following were prepared in the same way (in each case n=1):

RCO Z R² Remarks % Yield MS R_(f) Eluant IR [cm^(−1]) N8 N—H AS4 62 ESI:(M − H)⁻ = 0.61 Ethyl acetate/ (KBr): C═O 482/4/6 (Br₂) methanol = 6/4(v/v) 1612.4, 1724.3; —OH, —NH— 3386.8; 3483.2 N15 N—H AS4 64 ESI: (M −H)⁻ = 0.10 Ethyl acetate/ (KBr): C═O 578/80/82 (Br₂); methanol = 8/2(v/v) 1703.0 (M + H)⁺ = 580/2/4 (Br₂); (M + Na)⁺ = 602/4/6 (Br₂) N23 N—HAS4 58 ESI: (M − H)⁻ = 0.33 Ethyl acetate/ (KBr): C═O 557/59/61/63(Br₂,Cl) methanol = 8/2 (v/v) 1616.3; 1724.3 N15 N—H AS1 No addition 59ESI: (M − H)⁻ = 0.72 EE/MeOH/ (KBr): C═O of sodium 579/81/83 (Br₂) NH₄OH= 6/4/1 1695.3 hydroxide (v/v/v) N66 N—H AS21 95 0.48 EE/AcOH (KBr): C═O10/0.02 (v/v) 1639 N66 CH₂ AS1 85 0.38 CH₂Cl₂/MeOH/ AcOH 9/1/0.15(v/v/v) N71 CH₂ AS1 66.6 ESI: (M + H)⁺ = 0.38 CH₂Cl₂/MeOH/ (KBr): C═O606/08/10 (Br₂) AcOH 9/1/0.15 1622/1680 (v/v/v) N66 N—H AS18 100 ESI: (M− H)⁻ = 0.26 EE/AcOH 9/0.01 557 (v/v) N66 N—H AS19 98 0.22 CH₂Cl₂/MeOH/(KBr): C═O AcOH 9/1/0.15 1665/1740 (v/v/v) N66 N—H AS5 73 ESI: (M − H)⁻= 0.23 FM1 (KBr): C═O 577/79/81 (Br₂) 1632/1705 N66 N—H AS22 78 0.30 FM1(KBr): C═O 1668/1739 N66 CH₂ AS21 79 0.34 EE/AcOH 9/0.01 (KBr): C═O(v/v) 1643/1703 N66 CH₂ AS1 90 0.30 EE/MeOH 9/1 (v/v) N15 CH₂ AS1 78ESI: (M − H)⁻ = 0.30 EE/AcOH 9/0.01 (KBr): C═O 578/80/82 (Br₂) (v/v)1728/1672 N66 N—H AS25 99 N66 CH₂ AS2 100 (KBr): C═O 1645/1712 N66 CH₂AS23 70 N139 CH₂ AS2 59 (KBr): C═O 1630/1662/1707 N66 CH₂ AS27 93 0.20FM1 N66 CH₂ AS28 LiOH 100 0.30 FM1 N66 CH₂ AS4 72 0.53 FM1 (KBr): C═O1639/1701 N66 CH₂ AS36 74 ESI: (M − H)⁻ = 0.36 FM1 (KBr): C═O 4341645/1701 N66 CH₂ AS38 69 N66 CH₂ AS48 47 EI: M⁺ = 489 0.30 FM1 (KBr):C═O 1645 N66 N—H AS49 47 0.10 FM1 N66 CH₂ AS18 60 0.15 EE N66 CH₂ AS3996 N109 CH₂ AS21 81 N113 CH₂ AS21 76 0.20 EE/AcOH 99/1 N134 CH₂ AS21 890.15 EE/AcOH 99/1 N66 CH₂ AS47 100 ESI: (M + H)⁺ = (KBr): C═O 4761645/1716 N66 CH₂ AS7 60 0.20 FM1 (KBr): C═O 1649/1722 N66 CH₂ AS52 95ESI: (M + H)⁺ = 0.15 FM1 (KBr): C═O 480 1643/1722

EXAMPLE A38

Preparation of compounds of general formula:

3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine

A mixture of 24 g (46.3 mmol) of methyl3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine and5.0 g (50 mmol) of lithium hydroxide in 200 ml of water was stirred for1 hour at 60 C. The solid product was suction filtered and the filtratewas washed with 200 ml of ethyl acetate. By the addition of 1 M aqueoushydrochloric acid the aqueous phase was adjusted to a pH of 3-4 andextracted 3 times with 150 ml of ethyl acetate. The combined ethylacetate phases were washed once with water, dried over sodium sulphateand evaporated down in vacuo. The residue was triturated with ether. 9.1g (38% of theory) of a colourless solid were obtained.

IR(KBr): 1719 cm⁻¹ (C═O)

R_(f): 0.57 (ethyl acetate/methanol/glacial acetic acid=9.5/0.5/0.2(v/v/v))

The following were prepared in the same way (in each case n=1):

RCO Z R² Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] N6 N—H AS1 100 0.20FM1 (KBr): C═O 1625.9; 1730 N15 N—H AS6 H₂O/MeOH = 85 ESI: (M − H)⁻ =0.53 EE/MeOH/AcOH = (KBr): C═O 1/1 (v/v) as solvent 501/3 (Br) 9/1/0.1(v/v/v) 1695.3 N2 N—H AS1 75 0.57 EE/methanol/glacial (KBr): C═O aceticacid = 1718.5 9.5/0.5/0.2 (v/v/v) N2 N—H AS2 71 0.20 FM1 (KBr): C═O1625.9; 1693.4; 1718.5; —NH— 3357.9 N15 N—H AS3 H₂O/MeOH = 57 0.30EE/MeOH = (KBr): C═O 1/1 (v/v) as solvent 1/1 (v/v) 1693.4 N66 AS1 750.05 EE/MeOH 8/2 N66 AS4 85 N122 AS1 44 N122 AS4 85 N66 N—CH₃ AS1 58ESI: (M − H)⁻ = 0.20 EE (KBr): C═O 607/09/11 (Br₂) 1607/1655/1711 N66N—H AS17 55 0.03 FM1 N15 CH₂ AS1 78 ESI: (M − H)⁻ = 0.30 EE/MeOH 9/1(KBr): C═O 578/80/82 (Br₂) (v/v) 1672/1728 N66 N—H AS23 79.0 0.22 FM1(KBr): C═O 1738/1664

EXAMPLE A39

methylN⁶-[(1,1-dimethylethoxy)carbonyl]-N²-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine

To a mixture of 10 g (19.4 mmol) of3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine,2.6 g (20 mmol) of DIEA, 6.4 g (20 mmol) of TBTU, 2.64 g (19.5 mmol) ofHOBt and 200 ml of dimethylformamide was added dropwise, with stirring,a solution of 5.04 g (19.4 mmol) of H-Lys(Boc)-OMe in 50 ml ofdimethylformamide and the mixture was stirred overnight at roomtemperature. The reaction mixture was evaporated down in vacuo and theresidue was taken up in 250 ml of ethyl acetate. The ethyl acetate phasewas then washed twice with 100 ml of saturated aqueous sodium hydrogencarbonate solution, once with 100 ml of 20% aqueous citric acid solutionand finally once with 100 ml of saturated aqueous saline solution. Theorganic phase was dried with sodium sulphate, evaporated down in vacuoand the residue was purified by column chromatography (MN-silica gel 60,Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/petroleumether=2/1 (v/v)). After removal of the solvent in vacuo the residue wastriturated with ether, the amorphous solid obtained (9.5 g; 66% oftheory) was suction filtered and dried.

IR(KBr): 1632; 1657, 1682, 1734 cm⁻¹ (C═O)

R_(f): 0.64 (ethyl acetate)

ESI-MS: (M+H)⁺=757/759/761 (Br₂) (M+Na)⁺=779/781/783 (Br₂)

EXAMPLE A40

N⁶-[(1,1-dimethylethoxy)carbonyl]-N²-[N-[[[2-(3-methoxy-phenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine

A mixture of 7.75 g (10.4 mmol) of methylN⁶-[(1,1-dimethyl-ethoxy)carbonyl]-N²-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine,3.5 g (140 mmol) of lithium hydroxide and 150 ml of water was stirredovernight at room temperature. The aqueous phase was washed once withethyl acetate, acidified by the addition of 1 M aqueous potassiumhydrogen sulphate solution and then extracted with ethyl acetate. Theorganic phase was dried over sodium sulphate and evaporated down invacuo. 6.9 g (91% of theory) of a yellowish oil were obtained.

IR(KBr): 1653 cm⁻¹ (C═O)

R_(f): 0.7 (ethyl acetate/methanol/glacial acetic acid=9/0.5/0.5(v/v/v))

ESI-MS: (M−H)⁻=741/743/745 (Br₂)

EXAMPLE A41

1-[N²-[N-(phenylmethoxycarbonyl)-3,5-dichloro-D-tyrosyl]-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

A mixture of 5 g (13.0 mmol) of3,5-dichloro-N-[(phenylmethoxy)carbonyl]-D-tyrosine, 5.1 g (13.0 mmol)of1-[N⁶-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,1.81 g (14 mmol) of DIEA, 4.17 g (13 mmol) of TBTU, 1.75 g (13.0 mmol)of HOBt and 200 ml of tetrahydrofuran was stirred at room temperatureovernight. The reaction mixture was evaporated down in vacuo, theresidue was taken up in ethyl acetate/methanol (95/5) and washed twicewith saturated aqueous sodium hydrogen carbonate solution. The organicphase was dried, evaporated down in vacuo and the residue was purifiedby column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 meshASTM, eluant: ethyl acetate/methanol=6/4 (v/v)). 6.0 g (61% of theory)of a yellowish oil were obtained.

R_(f): 0.47 (FM1)

ESI-MS: (M+H)⁺=757/759/761 (Cl₂)

EXAMPLE A42

Preparation of compounds of general formula:

1-[N²-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(1,1-dimethylethoxy)-carbonyl]-L-lysyl]-4-(1-methyl-4-piperidinyl)-piperazine

To a mixture of 1.1 g (1.5 mmol) ofN⁶-[(dimethylethoxy)-carbonyl]-N²-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine,0.79 g (6.1 mmol) of DIEA, 0.52 g (1.6 mmol) of TBTU, 0.2 g (1.5 mmol)of HOBt and 100 ml of dimethylformamide was added dropwise a solution of0.44 g (1.5 mmol) of 1-(1-methyl-4-piperidinyl)-piperazine in 30 ml ofdimethylformamide at room temperature, the mixture was then stirredovernight and evaporated down in vacuo. The residue was taken up inethyl acetate/methanol (95/5), washed twice with 70 ml of aqueoussaturated sodium hydrogen carbonate solution, dried over sodium sulphateand evaporated down in vacuo. 1.1 g (81% of theory) of a colourless foamwere obtained.

R_(f): 0.34 (ethyl acetate/methanol/conc. aqueous ammonia=7/2/1 (v/v/v))

The following was prepared analogously (n=1):

Re- % Elu- RCO R² A NR³R⁴ marks Yield R_(f) ant IR [cm⁻¹] N15 AS1 A11 C1KHSO₄ 70 0,40 FM3 (KBr): solution C═O 1697.3; 1641.3

EXAMPLE A43

1-[N²-(3,5-dichloro-D-tyrosyl)-N⁶-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

A solution of 6 g (7.9 mmol) of1-[N²-[N-[(phenylmethoxy)carbonyl]-3,5-dichloro-D-tyrosyl]-N⁶-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazinein a mixture of 200 ml of methanol and 20 ml of aqueous 1 M potassiumhydrogen sulphate solution was hydrogenated in the presence of 0.5 gpalladium black as catalyst at room temperature under 3 bar of hydrogenpressure for 40 minutes. The catalyst was filtered off, the reactionmixture was evaporated to dryness in vacuo and the residue adjusted to apH of about 10 by the addition of 2 ml of concentrated aqueous ammoniasolution. The product was extracted several times with isopropanol, thecombined isopropanel extracts were evaporated down in vacuo and theresidue was purified by column chromatography (LiChroprep, Si60 particlesize: 20-40 μm, Messrs. Merck (Darmstadt); eluant: methylenechloride/methanol/ammonia=350/75/75/10 (v/v/v/v)). 2.5 g (51% of theory)of a colourless amorphous solid substance were obtained.

IR(KBr): 1641, 1705 cm⁻¹ (C═O)

R_(f): 0.27 (FM1)

EXAMPLE A44

Preparation of compounds of general formula:

Fmoc-A-NR³R⁴

1-[N²-[(9-fluorenylmethoxy)carbonyl]-N^(G)-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl)-piperazine

To a mixture of 7.0 g (10.6 mmol) of Fmoc-Arg(Pmc)-OH, 1.42 g (11.0mmol) of DIEA, 3.53 g (11.0 mmol) of TBTU, 1.35 g (11.0 mmol) of HOBtand 50 ml of DMF was added dropwise with stirring a solution of 1.74 g(10.6 mmol) of 1-(4-pyridinyl)-piperazine in 20 ml of DMF. The reactionmixture was stirred for a further 3.5 hours at room temperature and thenevaporated down at 40° C. in a high vacuum. The residue was dissolved inethyl acetate, the organic phase was washed twice with saturated aqueoussodium hydrogen carbonate solution, dried over sodium sulphate andevaporated down in vacuo. The residue was triturated with diethylether,suction filtered and dried. 7.85 g (96% of theory) of the desired endproduct were obtained, which was reacted without further purification.

R_(f): 0.5 (FM1)

The following was prepared analogously:

% A NR³R⁴ Yield R_(f) Eluant IR [cm⁻¹] A3 C18 60 0.55 FM4 (KBr): C═O1643; 1711

EXAMPLE A45

Preparation of compounds of general formula:

H-A-NR³R⁴

1-[N^(G)-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl)-piperazine

A solution of 8.5 g (11.1 mmol) of1-[N²-[(9-fluorenylmethoxy)carbonyl]-N^(G)-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl)-piperazinein 100 ml of THF was mixed with 16 ml of diethylamine and then stirredfor 2.5 hours at room temperature. The reaction mixture was evaporateddown in vacuo and the residue was purified by column chromatography(MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: FM1). 3.3 g(54% of theory) of an amorphous solid were obtained.

R_(f):=0.19(FM1)

IR(KBr) 1637 cm⁻¹ (C=O)

The following was prepared analogously:

% A NR³R⁴ Yield R_(f) Eluant IR [cm⁻¹] A3 C18 80 (KBr): C═O 1637.5; 1705

EXAMPLE A46

1-[N⁶,N⁶-dimethyl-N²-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

9.6 g (18.3 mmol) of1-[N⁶-[(1,1-dimethylethoxy)carbonyl]-N²-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazinewere stirred overnight in 200 ml of a 5% solution of trifluoroaceticacid in dichloromethane. The reaction mixture was then evaporated downin vacuo. 13.47 g (97% of theory) of the desired1-[N²-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine wereobtained as the trifluoroacetate salt. Then 7.0 g (9.1 mmol) of thecrude product were dissolved in 200 ml of water and 4.1 ml of a 40%formaldehyde solution (45.6 mmol) were added whilst cooling with an icebath. The reaction mixture was stirred for 10 minutes at roomtemperature, carefully mixed with 1.5 g (40 mmol) of sodium borohydridewhilst cooling with an ice bath, then mixed with 4.1 ml of a 40%formaldehyde solution (45.6 mmol) whilst cooling externally with ice,after which the reaction mixture was stirred for a further 10 minutes atroom temperature and again mixed with 1.5 g (40 mmol) of sodiumborohydride whilst cooling with an ice bath. The pH of the reactionmixture was monitored continuously during the reaction and kept betweenpH 3 and pH 6 by dropwise addition of trifluoroacetic acid. The mixturewas then stirred for 30 minutes at 5° C., adjusted to pH 10 by theaddition of potassium carbonate and extracted four times with 50 ml ofethyl acetate. The combined organic phases were dried, evaporated downin vacuo and the residue was purified by column chromatography(MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethylacetate/methanol/conc. aqueous ammonia=6.5/3/0.3 (v/v/v)). 2.3 g (56% oftheory) of a colourless oil were obtained.

IR(KBr): 1711, 1649 cm⁻¹ (C═O)

R_(f): 0.2 (FM7)

ESI-MS: (M+H)⁺=454

EXAMPLE A47

Preparation of compounds of general formula:

methyl(R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoate

A mixture of 10 g (27 mmol) of methyl4-amino-3,5-dibromo-γ-oxo-benzenebutanoate, 5.4 g (27 mmol) of4-(4-pyridinyl)-piperidine and 1.5 g (45 mmol) of paraformaldehyde wassuspended in 20 ml of glacial acetic acid and heated with stirring in anoil bath (bath temperature: 100° C.). After 3 hours a further 1.5 g (45mmol) of paraformaldehyde were added and the mixture was stirred for afurther 3 hours at 100° C. and then for 1 hour at 125° C. The solventwas removed in vacuo and the residue was taken up in 800 ml of water.The aqueous phase was made alkaline by the addition of sodium carbonateand extracted twice with 500 ml of ethyl acetate. The combined ethylacetate extracts were dried, evaporated down in vacuo and the residuewas purified by column chromatography (MN-silica gel 60, Macherey Nagel,70-230 mesh ASTM, eluant: ethyl acetate/methanol=9:1)). 1.0 g (6.8% oftheory) of the desired end product were obtained as an oil.

IR(KBr): 1716.5 cm−1

R_(f): 0.7 (FM1)

The following was prepared analogously:

% A NR³R⁴ Yield R_(f) Eluant IR [cm⁻¹] AS4 C8 35 0.68 FM1 (KBr): C═O1672.2; 1733.9

EXAMPLE A48

Preparation of compounds of general formula:

(R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoicacid

A mixture of 1.0 g (1.9 mmol) of methyl(R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-phenylbutanoate,5 ml of 1 N sodium hydroxide solution and 50 ml of dioxane was stirredovernight at room temperature and for 1 hour at 60° C. The reactionmixture was then neutralised by the addition of 5 ml of 1 N hydrochloricacid, evaporated down in vacuo and the residue was dried in a vacuumdrying chamber. 0.97 g (100% of theory) of the desired product wasobtained, which was further reacted without any purification.

R_(f): 0.15 (FM1)

The following was prepared analogously:

% A NR³R⁴ Yield R_(f) Eluant IR [cm⁻¹] AS4 C8 96 0.2 FM1 (KBr): C═O 1660

EXAMPLE A49

3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid

To a solution of 12 g (0.043 mol) of4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 200 ml of aceticacid were added 150 ml of water and 8 g of sodium acetate, a solution of5 ml of bromine in 60 ml of acetic acid was added dropwise withstirring, then the reaction mixture was extensively evaporated down invacuo and the residue was stirred into water. The aqueous phase wasrepeatedly extracted with ethyl acetate, and the combined organic phaseswere washed with water. The organic extracts were dried, evaporated downin vacuo and the solid residue was recrystallised from diisopropylether.12 g (70% of theory) of the desired end product were obtained.

R_(f): 0.4 (ethyl acetate/petroleum ether/glacial acetic acid=5/5/0.4(v/v/v)

ESI-MS: (M+H)⁺=394/6/8 (Br₂)

EXAMPLE A50

Preparation of compounds of general formula:

methyl(R,S)-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]-4-oxo-butanoate

A solution of 2.0 g (5 mmol) of3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 80 mlof THF was mixed with 1.6 g (5 mmol) of TBTU, 0.76 g (5 mmol) of HOBt,1.25 g (5 mmol) of 4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)piperidineand 1.03 g (8 mmol) of DIEA with stirring. The reaction mixture wasstirred for 6 hours at room temperature and then evaporated down invacuo. The residue was mixed with saturated aqueous sodium hydrogencarbonate solution and extracted several times with ethyl acetate. Thecombined organic extracts were washed successively with saturatedaqueous sodium hydrogen carbonate solution and water, dried over sodiumsulphate and evaporated down in vacuo. 3.0 g (50% of theory) of thedesired product was obtained, which was further reacted withoutpurification.

IR(KBr): 1714.8 cm⁻¹ (C═O)

R_(f): 0.7 (ethyl acetate/petroleum ether=7/3 (v/v))

The following were prepared analogously:

RCO R² % Yield MS R_(f) Eluant IR [cm⁻¹] N66 AS1 98 0.66 FM1 N66 AS2 1000.77 FM1 (KBr): C═O 1664/1734 N139 AS2 100 EI: M⁺ = 0.30 FM1 (KBr): C═O486 1643/1672/1732 N66 AS4 28 EI: M⁺ = 0.33 FM4 (KBr): C═O 606/08/101666/1734 (Br₂) N66 AS36 63 0.56 FM4 N66 AS38 92 N66 AS48 100 0.68 FM1N66 AS18 22 N66 AS39 100 N109 AS21 39 0.35 EE (KBr): C═O 1639/1734 N113AS21 57 0.15 EE/PE 95/5 N134 AS21 80 0.15 EE N66 AS7 100 0.75 FM1 N66AS53 40

EXAMPLE A51

(R)-1-[2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propyl]-4-(1-piperidinyl)-piperidine

To a suspension of 3.8 g (100 mmol) of lithium aluminium hydride in 400ml of THF were added in batches, with stirring and at room temperature,14.4 g (20 mmol) of1-(3,5-dibromo-D-tyrosyl)-4-(1-piperidinyl)-piperidine within 30minutes. The reaction mixture was kept for 30 minutes at roomtemperature and refluxed for 2 hours and then neutralised by the carefuladdition of 1 ml of water and 5.1 ml of concentrated aqueoushydrochloric acid. After the addition of 100 ml of methanol the solidprecipitate was suction filtered and the filtrate was evaporated down invacuo. The residue was purified by column chromatography (MN-silica gel60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylenechloride/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 5.4 g (57% oftheory) of the desired product was obtained as an amorphous solid.

IR (KBr): 3420 cm⁻¹ (NH₂)

R_(f): 0.4 (FM2)

ESI-MS: M⁺=473/475/477 (Br₂)

The following was prepared analogously:

(R)-1-[2-amino-3-(4-amino-3,5-dibromophenyl)propyl]-4-1-piperidinyl)-piperidine from1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(1-piperidinyl)-piperidine in ayield of 56.5%. of theory, R_(f) 0.12 (eluant:dichloromethane/methanol/cyclohexane/conc. ammonia 7/1.5/1.5/0.2(v/v/v/v)).

EXAMPLE A52

(R)-1-[3-(4-amino-3,5-dibromophenyl)-2-[N-[(1,1-dimethylethoxy)carbonyl]amino]propyl]-4-(1-piperidinly)-piperidne

To a solution of 10 g (0.017 mol) of1-[4-amino-3,5-dibromo-N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidinein 350 ml of dioxane were added 3.1 g (0.082 mol) of sodium borohydrideand the reaction mixture was cooled to 5° C. Then a solution of 4.92 g(0.082 mol) of acetic acid in 100 ml of dioxane was added dropwise withstirring. The reaction mixture was stirred for a further hour at roomtemperature and for 3 hours at 85° C. Then ice water was added, theorganic solvent was removed in vacuo and the aqueous residue wasrepeatedly extracted with methylene chloride. The combined organicphases were dried, evaporated down in vacuo and the residue was purifiedby column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 meshASTM, eluant: methylene chloride/methanol/cyclohexane/conc. aqueousammonia=3600/150/150/20 (v/v/v/v). 4.1 g (42% of theory) of a colourlessfoam were obtained.

IR(KBr): 1705 cm⁻¹ (C═O)

EXAMPLE A53

(R)-1-[2-amino-3-(4-amino-3,5-dibromophenyl)propyl]-4-(1-piperdinyl)-piperidine

To a mixture of 4 g (7 mmol) of(R)-1-[3-(4-amino-3,5-dibromophenyl)-2-[N-[(1,1-dimethylethoxy)carbonyl]-amino]propyl]-4-(1-piperidinyl)-piperidineand 100 ml of methylene chloride, 40 ml of trifluoroacetic acid wereslowly added dropwise, with stirring, at 10° C. The reaction mixture wasstirred for 2 hours at room temperature and then evaporated down invacuo. The residue was mixed with ice water, made basic by the additionof concentrated aqueous ammonia solution and extracted three times with200 ml of diethylether. The combined ether extracts were dried andevaporated down in vacuo. 3.4 g (100% of theory) of an amorphous solidwere obtained.

IR(KBr): 1683.8, 1616.3 (C═O)

R_(f): 0.02 (FM 4)

EXAMPLE A54

methyl(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)phenyl]-methyl]-butanoate

Prepared analogously to Example A15a) from methyl(R,S)-3-carboxy-2-[[3-(trifluoromethyl)phenyl]methyl]-propanoate and3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a yield of 27.3% oftheory. Colourless, amorphous substance, R_(f)=0.25 (eluant: ethylacetate).

MS: M⁺=503

The following was obtained in the same way:

methyl(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoatefrom methyl(R,S)-3-carboxy-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-propanoate and3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a yield of 98% oftheory, R_(f)=0.66 (eluant: dichloromethane/cyclohexane/methanol conc.ammonia 7/1.5/1.5/0.2 (v/v/v/v)).

EXAMPLE A55

(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoicacid

A mixture of 3.0 g (4.92 mmol) of methyl(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoate,30 ml (30 mmol) of 1N sodium hydroxide solution and 20 ml of methanolwas stirred for 3 hours at room temperature, then diluted with 100 ml ofwater and 30 ml of 1N hydrochloric acid were added dropwise. Theprecipitate was suction filtered and dried at 50° C. in a circulatingair drier. Colourless, amorphous substance , R_(f)=0.38 (eluant:dichloromethane/methanol/glacial acetic acid 9/1/0.15 (v/v/v)). Yield:2.5 g (85.4% of theory).

The following was obtained in the same way:

(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl-4-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-butanoicacid from methyl(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-butanoatein a yield of 79% of theory, R_(f)=0.34 (eluant: ethyl acetate/glacialacetic acid 99.8/0.2 (v/v)).

IR(KBr): 1703, 1643 cm⁻¹ (C═O)

EXAMPLE A56

Methyl3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-1-N-methyl-D-tyrosine

a) 1-(chlorocarbonyl)-4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]piperidine

To a mixture of 7.0 ml (about 14 mmol) of a 20% solution of phosgene intoluene and 2.02 g (20 mmol) of triethylamine in 300 ml oftetrahydrofuran was added in batches, while maintaining a reactiontemperature of about 0° C., a suspension of 1.5 g (5.60 mmol) of4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]piperidine-hydrochloride in 100ml of tetrahydrofuran. The mixture was stirred for another hour at atemperature between 0° C. and +5° C., filtered to remove the resultingtriethylamine-hydrochloride and the filtrate was freed from solvent. Theresidue was triturated with diisopropyl ether and suction filtered.After drying in vacuo 0.7 g (42.6% of theory) of colourless crystalswere obtained, R_(f)=0.17 (eluant: dichloromethane/acetone 9.5/0.5(v/v)), which was further processed without any further purification.

b) Methyl3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-N-methyl-D-tyrosine

To a solution of 4.9 g (13.3 mmol) of methyl3,5-dibromo-N-methyl-D-tyrosine and 4.04 g (40 mmol) of triethylamine in500 ml of tetrahydrofuran was added dropwise, at room temperature,within 3 hours, a solution of 3.92 g (13.34 mmol) of1-(chlorocarbonyl)-4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]piperidine in1 l tetrahydrofuran. The mixture was then heated for 12 hours to refluxtemperature, left to cool and filtered to remove the precipitatedtriethylamine. The filtrate was evaporated down, the residue was dividedbetween ethyl acetate and 20% aqueous citric acid. The organic phase wasdried over sodium sulphate, again evaporated down in vacuo, the residuewas purified by column chromatography over silica gel using ethylacetate/petroleum ether 9/1 (v/v) as eluant. Working up the appropriatefractions yielded 3.2 g (38.5% of theory) of a colourless, amorphoussubstance, R_(f)=0.45 (eluant: ethyl acetate).

IR(KBr): 1739.7, 1660.6 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=623/625/627 (Br₂) (M+Na)⁺=645/647/649 (Br₂)(M+K)⁺=661/663/665 (Br₂)

EXAMPLE A57

Methyl 3,5-dibromo-4-methoxy-D-phenylalanine

To a mixture of 5.5 g (14.12 mmol) of3,5-dibromo-4-methoxy-D-phenylalanine-hydrochloride and 55 ml ofmethanol were added 150 ml of a saturated methanolic hydrogen chloridesolution and the mixture was stirred for 20 hours at room temperature.The residue remaining after evaporation of the solvent was stirred with50 ml of water and adjusted to pH 8 with saturated sodium hydrogencarbonate solution. The precipitate was suction filtered, stirred with10 ml of isopropanol and left to stand overnight. The insoluble matterwas filtered off and the filtrate was evaporated down in vacuo. Theresidue was further reacted as a crude product. Yield: 1.0 g (28.7% oftheory) of a colourless oil , R_(f)=0.55 (eluant: dichloromethane/ethylacetate/cyclohexane/methanol/conc. ammonia=300/80/25/25/3 (v/v/v/v/v)).

EXAMPLE A58

1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine

a) 1-(2-chloro-4-pyrimidinyl)-4-(phenylmethyl)piperazine

A mixture of 9.9 g (0.0664 mol) of 2,4-dichloropyrimidine, 200 ml ofwater and 11.7 ml (0.0673 mol) of 1-(phenylmethyl)piperazine was heatedto 40° C. for 2 hours in an ultrasound bath. After cooling the mixturewas made alkaline with potassium carbonate and extracted thoroughly withethyl acetate. The crude product obtained after working up in the usualway was purified by column chromatography over silica gel (30-60 μm)using FM2 and FM4 (2/1 v/v) as eluant. Working up the appropriatefractions yielded 7.4 g (38.6% of theory) of a colourless oil,R_(f)=0.51 (FM4; Macherey-Nagel POLYGRAMO® SIL G/UV₂₅₄, ready-made filmsfor TLC).

MS: M⁺=288/290 (Cl)

b) 1-(4-pyrimidinyl)piperazine

A solution of 7.4 g (0.0256 mol) of1-(2-chloro-4-pyrimidinyl)-4-(phenylmethyl)piperazine in 100 ml ofethanol was hydrogenated in the presence of 2 g of 10%palladium/charcoal for 4 hours at 40° C. under 5 bar of hydrogenpressure. The crude product obtained after conventional working up waspurified by column chromatography over silica gel (30-60 μm) usingFM1/cyclohexane 9/1 (v/v) as eluant. Colourless crystals, R_(f)=0.3(FM1/cyclohexane 9/1 (v/v)); Macherey-Nagel POLYGRAM® SIL G/UV₂₅₄,ready-made films for TLC). Yield: 1.7 g (40.7% of theory).

c)1-[4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine

Prepared analogously to Example A15a) from4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanine and1-(4-pyrimidinyl)piperazine in the presence of TBTU in a yield of 92% oftheory. Colourless, amorphous substance, R_(f)=0.42 (FM4; Macherey-NagelPOLYGRAM® SIL G/UV₂₅₄, ready-made films for TLC).

IR(KBr): 1705.0, 1643.3 cm⁻¹ (C═O)

MS: M⁺=582/584/586 (Br₂)

d) 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine

Prepared analogously to Example A1b) from1-[4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanyl)-4-(4-pyrimidinyl)piperazinein a yield of 52% of theory. Colourless, amorphous substance, R_(f)=0.55(FM1; Macherey-Nagel POLYGRAM® SIL G/UV₂₅₄, ready-made films for TLC).

IR(KBr): 1681.8 cm⁻¹ (C═O)

MS: M⁺=482/484/486 (Br₂)

EXAMPLE A59

Preparation of compounds of general formula:

(R,S)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidin]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-4-oxobutanoicacid

A mixture of 4.8 g (8.3 mMol) of ethyl4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-2-(ethoxycarbonyl)-4-oxobutanoate,200 ml of ethanol and 41.5 ml of 1N sodium hydroxide solution wasrefluxed for 3 hours. The ethanol was removed in vacuo, then the residuewas diluted with 50 ml of water and adjusted to pH 3 with 1N aqueoushydrochloric acid. The precipitated substance was suction filtered,thoroughly washed with water and then dried in vacuo. 3.8 g (96% oftheory) of colourless crystals of Mp. 139 141° C. were obtained,R_(f)=0.65 (eluant: EE/MeOH/glacial acetic acid 90/10/1 v/v/v).

IR(KBr): 1724, 1647 cm⁻¹ (C═O)

MS: no M⁺, m/e=246, 231, 147

The following were prepared analogously:

R² Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] AS29 100 AS16 17 ESI: (M +H)⁺ = 0.30 EE/MeOH/ 488/90/92 (Cl₂) AcOH 80/10/1 AS5 62 0.60CH₂Cl₂/MeOH/ NH₄OH 90/10/1 AS32 100 ESI: (M + Na)⁺ = 0.67 EE/MeOH/(KBr): C═O 614/6/8 (Br₂) AcOH 90/10/1 1645/1728 AS33 90 EI: M⁺ = 5250.20 EE/MeOH/ (KBr): C═O AcOH 90/10/1 1643/1701 AS31 100 0.20CH₂Cl₂/MeOH/ NH₄OH 80/20/1 AS17 100 ESI: (M + H)⁺ = 0.50 EE/MeOH/ (KBr):C═O 608/10/12 (Br₂) AcOH 90/10/1 1643 AS34 76 ESI: (M − H)⁻ = 0.65EE/MeOH/ 506 AcOH 90/10/1 AS19 70 0.46 EE/MeOH/ (KBr): C═O AcOH 9/1/0.51643/1701 AS46 78 ESI: (M − H)⁻ = 0.20 FM1 (KBr): C═O 471 1647 AS50 970.05 EE AS2 LiOH instead 86 ESI: (M + H)⁺ = (KBr): C═O of NaOH 4721643/1705 AS29 100 ESI: (M − H)⁻ = (KBr): C═O 448 1645/1705 AS31 87

EXAMPLE A60

Preparation of compounds of general formula:

Ethyl4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-2-(ethoxycarbonyl)-4-oxobutanoate

A mixture of 2.31 g (10 mMol) of4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-piperidine, 3.64 g (10 mMol) ofβ,β-bis(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoic acid, 5 mlof triethylamine, 3.5 g (11 mMol) of TBTU, 200 ml of tetrahydrofuran and20 ml dimethylformamide was stirred for 5 hours at room temperature. Thesolvent was removed in vacuo and the residue taken up indichloromethane, the resulting solution was dried over sodium sulphateand freed from the solvent. After purification by column chromatographyon 400 g of silica gel (Amicon, 35-70 μm, ethyl acetate as eluant), 4.8g (83% of theory) of a colourless, amorphous substance were obtained,R_(f)=0.63 (eluant: EE).

IR(KBr): 1734, 1668, 1653 cm⁻¹ (C═O)

MS: M⁺=577 (Br₂)

The following were prepared analogously:

% R² Yield MS R_(f) Eluant IR [cm⁻¹] AS29 75 0.8 FM1 AS16 59 0.5 EE AS565 EI: M⁺ = 0.7 FM4 (KBr): C═O 677/79/81 1649/1668/ (Br₂) 1734 AS32 740.5 FM4 (KBr): C═O 1647/1668/ 1734 AS33 85 0.5 EE (KBr): C═O 1649/1734AS31 82 EI: M⁺ = 574 0.5 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 90/10/1 1658/1741AS17 93 EI: M⁺ = 0.5 EE (KBr): C═O 707/09/11 1645/1666/ (Br₂) 1736/1759AS34 75 EI: M⁺ = 607 0.8 EE (KBr): C═O 1649/1668/ 1736 AS19 67 0.8 FM1(KBr): C═O 1647/1668/ 1734 AS46 80 EI: M⁺ = 572 0.8 FM1 (KBr): C═O 1737AS50 78 EI: M⁺ = 0.6 EE (KBr): C═O 677/9/81 (Br₂) 1645/1666/ 1730 AS2 51

EXAMPLE A61

Preparation of compounds of general formula:

β,β-bis-(ethoxycarbonyl)-1-methyl-1H-indol-3-butanoic acid

Produced analogously to Example A1b) from tert.-butylβ,β-bis(ethoxycarbonyl)-1-methyl-1H-indol-3-butanoate through the actionof trifluoroacetic acid in dichloromethane in a yield of 63.5% oftheory. Colourless crystals of Mp. 127-130° C. (diisopropylether).

IR(KBr): 1738, 1712 cm⁻¹ (C═O)

The following were prepared analogously:

R² % Yield MS R_(f) Eluant IR [cm⁻¹] AS29 100 AS16 100 0.7 EE/MeOH/ AcOH97.5/2.2/0.25 AS5 100 0.5 PE/EE 2/1 AS32 100 0.58 PE/EE 2/1 (KBr): C═O1759/1711 AS33 100 (KBr): C═O 1736 AS17 52 (KBr): C═O 1707/1726/ 1755AS34 90 0.8 EE/MeOH/ (KBr): C═O AcOH 1705/1743 97.5/2.5/0.25 AS19 1000.76 PE/EE/ (KBr): C═O AcOH 6/3/1 1738 AS46 92 0.35 FM1 (KBr): C═O 1732AS50 71 (KBr): C═O 1712/1734/ 1759 AS2 31 EI: M⁺ = 272 0.42 PE/EE/(KBr): C═O AcOH 6/4/0.2 1711/1734

EXAMPLE A62

Preparation of compounds of general formula:

Tert.-butyl β,β-bis-(ethoxycarbonyl)-3,5-dimethylbenzene-butanoate

To a solution of 13.8 g (50.2 mMol) of diethyl[(1,1-dimethylethoxycarbonyl)methyl]-malonoate in 400 ml of anhydroustetrahydrofuran, 2.3 g (52.7 mMol) of sodium hydride was added whilstbeing externally cooled with iced water. After stirring for 30 minutes,and maintaining a reaction temperature of 0 to +5° C., the solution of10.0 g (50.2 mMol) of 3,5-dimethylbenzylbromide in 80 ml tetrahydrofuranwas added dropwise and the mixture allowed to warm to room temperaturewithin 14 hours. The reaction mixture was freed from the solvent invacuo, 200 ml of 10% citric acid was added to the residue and theresulting mixture was thoroughly extracted with ethyl acetate. After theusual working up, the combined extracts yielded 19.7 g (100% of theory)of a colourless oil of R_(f)=0.67 (eluant: dichloromethane), which wasused in the following steps without further purification.

The following were prepared analogously:

R² Remarks % Yield MS R_(f) Eluant IR [cm⁻¹] AS29 100 AS16 62 0.6 CH₂Cl₂AS5 91 ESI: (M + H)⁺ = 0.8 PE/EE (KBr): C═O 521/3/5 (Br₂) 2/1 1734 AS3296 0.76 PE/EE (KBr): C═O 2/1 1734 AS33 78 0.55 CH₂Cl₂ (KBr): C═O 1736AS31 with use of 3- 74 EI: M⁺ = 417 0.7 toluene/ (KBr): C═O(dimethylaminomethyl)- t-BME 4/1 1734 1-methyl-1H-indol- methoiodideAS17 70 EI: M⁺ = 0.5 CH₂Cl₂ (KBr): C═O 550/52/54 (Br₂) 1734 AS34 93 EI:M⁺ = 450 0.5 CH₂Cl₂/ (KBr): C═O PE 1/1 1736 AS19 87 0.89 CH₂Cl₂ (KBr):C═O 1736 AS46 54 EI: M⁺ = 415 0.7 FM4 AS50 60 EI: M⁺ = 0.7 CH₂Cl₂ (KBr):C═O 520/22/24 (Br₂) 1734

EXAMPLE A63

(phenylmethyl)-β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)benzenebutanoate

Prepared analogously to Example A62 fromdiethyl[(phenylmethoxycarbonyl)methyl]-malonoate and4-(1,1-dimethylethyl)benzylbromide in the presence of sodium hydride ina yield of 53% of theory.

Colourless oil of R_(f)=0.21 (eluant: dichloromethane/petroleum ether2/1 v/v).

IR(KBr): 1738 cm⁻¹ (C═O)

EXAMPLE A64

Methyl4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-4-oxobutanoate

To a solution of 2.0 g (4.43 mMol) of methyl4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-hydroxyphenyl)methyl]-4-oxobutanoatein 30 ml of anhydrous dimethylformamide, 0.2 g (4.4 mMol) of a 55%suspension of sodium hydride in paraffin oil was added. After stirringfor 30 minutes at room temperature, 0.5 ml (4.8 mMol) of isopropyliodidewas added dropwise, and kept for two hours each at room temperature andat 70° C. The residue remaining after removal of the volatileconstituents was divided between water and ethyl acetate. The organicphase was washed with saturated sodium chloride solution, dried overmagnesium sulphate and was again evaporated down. The raw product waspurified by column chromatography on silica gel (60 μm), first usingdichloromethane, later methanol/conc. ammonia (9/1 v/v) as eluants.Yield was 0.9 g (42% of theory) of a colourless, amorphous substance ofR_(f)=0.32 (FM4).

IR(KBr): 1734, 1668 cm⁻¹ (C═O)

MS: M⁺=493

In the same way, methyl4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-ethoxyphenyl)methyl]-4-oxobutanoatewas obtained from methyl4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-hydroxyphenyl)methyl]-4-oxobutanoateand ethyliodide in a yield of 67% of theory. Colourless, amorphoussubstance of R_(f)=0.29 (FM4).

IR(KBr): 1734, 1666 cm⁻¹ (C=O)

MS: M⁺=479

EXAMPLE A65

β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoic acid

Prepared analogously to example A58b) from phenyl methylβ,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoate bycatalytic hydrogenation in the presence of palladium/charcoal in a yieldof 95% of theory. Colourless, highly-viscous oil of R_(f)=0.16 (eluant:dichloromethane).

IR(KBr): 1739 cm⁻¹ (C═O)

EXAMPLE A66

1-methyl-4-[(1-piperazinyl)carbonyl]-piperazine-bis-(trifluoroacetate)

a)4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-1-methylpiperazine

To a solution of 1.1 g of triphosgene (3.7 mMol) in 20 ml ofdichloromethane, a mixture of 1.2 g (10 mMol) of 1-methyl-piperazine,0.38 ml (22 mMol) of DIEA and 35 ml of dichloromethane was addeddropwise at room temperature within 30 minutes, and then the solution of1.9 g (10 mMol) of 1-(1,1-dimethylethoxycarbonyl)piperazine and 0.38 mlof DIEA in 20 ml dichloromethane were added. After stirring for an hourat room temperature, insoluble matter was filtered off and the filtrateevaporated down in vacuo. After purification of the raw product onsilica gel (Amicon, 35-70 μm), using dichloromethane/methanol/conc.ammonia(80/20/1 v/v/v) for elution, 700 mg (22% of theory) of colourlesscrystals were obtained of Mp. 130° C.

IR(KBr): 1691, 1641 cm⁻¹ (C═O)

b)1-methyl-4-[(1-piperazinyl)carbonyl]-piperazine-bis-(trifluoroacetate)

Prepared analogously to Example A1b), but omitting the treatment withaqueous ammonia, from4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-1-methylpiperazineand trifluoroacetic acid in a yield of 99.6% of theory. Colourless,amorphous substance of R_(f)=0.17 (eluant:dichloromethane/methanol/conc. ammonia 50/50/0.5).

IR(KBr): 1678 cm⁻¹ (C═O)

MS: M⁺=212

EXAMPLE A67

1-[4-[4-(dimethylamino)butyl]phenyl]-piperazine-dihydrochloride

a) N,N-dimethyl-4-fluoro-γ-oxobenzenebutanoic acid amide

To a solution of 30.5 g (0.155 Mol) of 4-fluoro-γ-oxobenzenebutanoicacid in 470 ml tetrahydrofuran, 35.0 g (0.216 Mol) ofN,N′-carbonyldiimidazole was added with stirring and at room temperatureand held at room temperature for a further 2.5 hours. Then, 13.7 g(0.304 Mol) of dimethylamine was added under strong external cooling bymeans of an ice-ethanol mixture. After the mixture had stood at roomtemperature for 12 hours, the solvent was removed in vacuo, the residuewas divided between dichloromethane and 10% aqueous citric acidsolution, the organic phase was dried over sodium sulphate and onceagain evaporated down in vacuo. After purification by columnchromatography (eluant: ethyl acetate) on silica gel the crude productyielded 30.22 g (87% of theory) of colourless crystals of

R_(f)=0.31 (eluant: ethyl acetate/glacial acetic acid 99.99/0.01).

IR(KBr): 1680, 1647 cm⁻¹ (C═O)

b) N,N-dimethyl-γ-oxo-4-[4-(phenylmethyl)-1-piperazinyl]-benzenebutanoicacid amide

The mixture of 33.48 g (0.15 Mol) ofN,N-dimethyl-4-fluoro-γ-oxobenzenebutanoic acid amide, 29.6 g (0.168Mol) of 1-(phenylmethyl)piperazine and 6 ml of DIEA was refluxed for 6hours. Another 30 g (0.17 Mol) of (phenylmethyl)piperazine was added,and the mixture was refluxed for a further 7 hours. The mixture wastaken up in a little dichloromethane, and purified by columnchromatography on silica gel, using dichloromethane/methanol/conc.ammonia 99/1/0.5 for elution. The residue obtained from the appropriatefractions was stirred with diisopropylether, the formed crystals werethen recrystallised from ethanol. 42.22 g (74% of theory) of colourlesscrystals were obtained, R_(f)=0.69 (eluant:dichloromethane/methanol/conc. ammonia 95/5/0.5 v/v/v).

IR(KBr): 1662, 1643 cm⁻¹ (C═O)

c)4-[4-[4-(dimethylamino)-1-hydroxybutyl]phenyl]-1-(phenylmethyl)piperazine

Prepared analogously to example A51 fromN,N-dimethyl-γ-oxo-4-[4-(phenylmethyl)-1-piperazinyl]-benzenebutanoicacid amide by reduction with lithium aluminium hydride in a yield of 61%of theory. Colourless, amorphous substance of R_(f)=0.62 (eluant: ethylacetate/methanol 1/1 v/v).

MS: M⁺=367

d) 1-[4-[4-(dimethylamino)butyl]phenyl]-piperazine-dihydrochloride

Prepared analogously to example A20b) from4-[4-[4-(dimethyl-amino)-1-hydroxybutyl]phenyl]-1-(phenylmethyl)piperazineby catalytic hydrogenation in the presence of palladium/charcoal andhydrochloric acid in a quantitative yield. Colourless, amorphoussubstance of Rf 0.37 (eluant: ethyl acetate/methanol 50/50/0.5 v/v/v).

B. PREPARATION OF THE FINAL COMPOUNDS EXAMPLE 1

Preparation of compounds of general formula:

1-[N-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine(No. 83)

A mixture of 2 g (3.44 mmol) of3,5-dibromo-N²-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]-carbonyl]-D-tyrosine,0.59 g (3.6 mmol) of 1-(4-pyridinyl)-piperazine, 1.27 g (3.96 mmol) ofTBTU, 0.47 g (3.44 mmol) of HOBt, 0.7 ml (3.96 mmol) of DIEA and 100 mltetrahydrofuran was stirred overnight at ambient temperature. Thereaction mixture was extracted once with saturated aqueous salinesolution, twice with saturated aqueous sodium hydrogen carbonatesolution and again with saturated aqueous saline solution. The organicphase was dried, evaporated down in vacuo and the crude product was thenpurified by column chromatography (MN-silica gel 60, Macherey-Nagel,70-230 mesh ASTM, eluant: ethyl acetate/methanol=9/1/(v/v/)). 550 mg(22% of theory) of an amorphous solid were obtained.

IR(KBr): 1601, 1636, 1696 cm⁻¹ (C═O)

R_(f): 0.67 (FM2)

ESI-MS: (M+H)⁺=726/728/730 (Br₂)

The following were prepared analogously (in each case n=1):

% No. RCO Z R² A NR³R⁴ Remarks Yield MS R_(f) Eluant IR [cm⁻¹] N6 N—HAS1 A3 C4 88 ESI: (M + H)⁺ = 0.8 FM1 (KBr): C═O 928/30/32 (Br₂) 1629.8;1708.8 193 N15 N—H AS6 A0 C7 DMF as solvent 26 ESI: (M + H)⁺ = 0.9EE/MeOH/AcOH (KBr): C═O 647/9 (Br) 75/23/2 v/v/v 1693.4; 1622.0 194 N66N—H AS1 A0 C67 49 ESI: (M + H)⁺ = 0.33 FM1 (KBr): C═O 828/30/32 (Br₂)1622/1664 202 N15 N—H AS1 A0 C36 DMF as solvent; 9 ESI: (M + H)⁺ = 0.49FM1 (KBr): C═O DIEA 733/5/7 (Br₂) 1695.3;1622.0 NH 3417.7 203 N15 N—HAS1 A0 C29 DMF as solvent; 41 ESI: (M − H)⁻ = 0.58 EE/MeOH (KBr): C═ODIEA 718/20/22 (Br₂) 9/1 v/v 1695.3 204 N15 N—H AS1 A0 C30 DMF assolvent; 27 ESI: (M + H)⁺ = 0.1 FM1 (KBr): C═O DIEA 691/3/5 (Br₂)1695.3; 1624.0 205 N15 N—H AS6 A0 C8 DMF as solvent; 23 ESI: (M + H)⁺ =0.46 FM1 (KBr): C═O DIEA 653/5 (Br) 1695.3; 1622.0 206 N15 N—H AS1 A0C31 DMF as solvent; 33 ESI: (M + H)⁺ = 0.25 FM1 (KBr): C═O DIEA717/19/21 (Br₂) 1695.3; 1624.0 207 N15 N—H AS1 A0 C32 DMF as solvent; 55ESI: (M − H)⁻ = 0.46 FM1 (KBr): C═O DIEA 780/2/4 (Br₂) 1690; 1650 212N15 N—H AS1 A7 C1 DMF as solvent; 37 ESI: (M + H)⁺ = 0.27 FM1 (KBr): C═ODIEA 882/4/6 (Br₂) 1697.3; 1639.4 NH 3423.4 217 N15 N—H AS6 A3 C1 51 0.9FM1 (KBr): C═O 1693.4; 1641.3 222 N15 N—H AS1 A0 C27 THF/DMF 1/1 10 ESI:(M + H)⁺ = 0.35 FM1 (KBr): C═O as solvent; 774/6/8 (Br₂) 1695.3 NEt₃ asbase 286 N15 N—H AS1 A0 C28 THF/DMF 1/1 9 ESI: (M + H)⁺ = 0.4 FM1 (KBr):C═O as solvent; 706/8/10 1699.2 NEt₃ as base (Br₂) 81 N15 N—H AS4 A0 C464 ESI: (M + H)⁺ = 0.75 FM1 (KBr): C═O 724/6/8 (Br₂); 1618.2; 1703.0(M + Na)⁺ = 746/48/50 (Br₂) 82 N15 N—H AS4 A0 C1 53 ESI: (M + H)⁺ = 0.55FM3 (KBr): C═O 725/7/9 (Br₂) 1620.1; 1703.0 84 N66 N—H AS21 A0 C68 31ESI: (M + H)⁺ = 0.52 FM1 (KBr): C═O 683 1608/1628/1666 85 N15 N—H AS4 A0C7 42 ESI: (M + H)⁺ = 0.8 FM1 (KBr): C═O 724/6/8 (Br₂); 1618.2; 1697.3;(M + Na)⁺ = —NH—, —NH₂ 3379.1 746/48/50 (Br₂) 90 N15 N—H AS1 A0 C8 40ESI: (M + H)⁺ = 0.78 FM2 (KBr): C═O 731/3/5 (Br₂) 1624.0; 1697.3 N2 N—HAS2 A3 C1 DMF as solvent; 73 ESI: (M + H)⁺ = 0.42 FM1 (KBr): C═O DIEA766 1654.2; 1708.8 354 N15 N—H AS1 A0 C4 21 ESI: (M + H)⁺ = 0.76 FM2(KBr): C═O 725/7/9 (Br₂); 1622.0; 1695.3; (M + Na)⁺ = —OH, —NH— 3417.7747/49/51 (Br₂) 98 N15 N—H AS1 A0 C9 60 ESI: (M + H)⁺ = 0.41 FM2 (KBr):C═O 580/2/4 (Br₂): 1624.0; 1685.7; (M − H)⁻ = —OH, —NH— 3421.5 578/80/82(Br₂); (M + Na)⁺ = 602/4/6 (Br₂) 102 N15 N—H AS1 A0 C12 43 ESI: (M + H)⁺= 0.76 FM2 (KBr): C═O 636/38/40 (Br₂); 1622.0; 1695.3; (M + Na)⁺ =658/60/62 (Br₂) 99 N15 N—H AS1 A0 C10 54 ESI: (M + H)⁺ = 0.61 FM2 (KBr):C═O 663/5/7 (Br₂) 1622.9; 1700.9; —OH,—NH— 3421.5 100 N15 N—H AS1 A0 C1154 ESI: (M + H)⁺ = 0.5 FM2 (KBr): C═O 746/48/50 (Br₂) 1624.0; 1695.3;—NH—, —OH 3423.4; 101 N15 N—H AS1 A0 C7 62 ESI: (M + H)⁺ = 0.82 FM2(KBr): C═O 725/7/9 (Br₂); 1622.0; 1695.3; (M + Na)⁺ = —OH, —NH— 3253.7747/49/51 (Br₂) 103 N15 N—H AS1 A0 C13 37 ESI: (M + H)⁺ = 0.72 FM2(KBr): C═O 679/81/83 (Br₂) 1625.9; 1693.4; 1666.4; —OH, —NH— 3409.9 106N15 N—H AS1 A0 C14 72 ESI: (M + H)⁺ = 0.66 FM1 (KBr): C═O 832/4/6 (Br₂);1674.1; 1689.5 (M + Na)⁺ = 854/6/8 (Br₂) 104 N15 N—H AS6 A0 C4 36 ESI:(M + H)⁺ = 0.71 FM1 (KBr): C═O 647/9 (Br); 1695.3 (M + Na)⁺ = 669/71(Br); (M − H)⁻ = 645/7 (Br) 105 N15 N—H AS6 A0 C1 25 ESI: (M + H)⁺ =0.25 FM3 (KBr): C═O 648/50 (Br) 1695.3 N2 N—H AS1 A12 C1 DMF as solvent;72 ESI: (M + H)⁺ = 0.4 FM1 KBr: C═O DIEA 1082/4/6 (Br₂) 1641 199 N15 N—HAS3 A0 C8 THF/DMF = 86 ESI: (M + H)⁺ = 0.37 ethyl acetate/ KBr: C═O 9/1(v/v) 643/5/7 (Br₂) methanol/ 1697; 1624 as solvent petroleum ether =1/2/1 (v/v/v) 200 N15 N—H AS3 A0 C1 40 ESI: (M + H)⁺ = 0.45 ethylacetate/ KBr: C═O 638/40/42 (Br₂) methanol/ 1695; 1636 petroleum ether =1/2/1 (v/v/v) 419 N66 N—H AS21 A0 C38 28 ESI: (M + H)⁺ = 0.1 FM1 (KBr):C═O 682 1628/1662 425 N66 N—H AS1 A0 C36 42 ESI: (M + H)⁺ = 0.4 FM1(KBr): C═O 747/49/51 (Br₂) 1624/1657 426 N66 N—H AS4 A0 C30 66 ESI: (M +H)⁺ = 0.45 FM1 (KBr): C═O 704/6/8 (Br₂) 1618/1663 427 N66 N—H AS1 A0 C3138 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 731/3/5 (Br₂) 1630/1653 428 N66N—H AS4 A0 C36 40 ESI:(M + H)⁺ = 0.6 FM1 (KBr): C═O 746/48/50 (Br₂)1618/1662 429 N66 N—H AS1 A0 C30 47 ESI: (M + H)⁺ = 0.15 FM1 (KBr): C═O705/7/9 (Br₂) 1635/1653 435 N66 N—H AS4 A0 C31 20 ESI: (M + H)⁺ = 0.55FM1 (KBr): C═O 730/2/4 (Br₂) 1608/1631 436 N66 N—H AS1 A0 C11 15 ESI:(M + H)⁺ = 0.1 FM1 (KBr): C═O 760/2/4 (Br₂) 1624/1653 437 N66 N—H AS4 A0C11 25 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O 759/61/63 (Br₂) 1622/1661 438N66 N—H AS4 A0 C54 13 ESI: (M + H)⁺ = 0.7 FM1 (KBr): C═O 744/6/8 (Br₂)1620/1660 439 N66 N—H AS1 A0 C54 31 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O745/7/9 (Br₂) 1626/1661 443 N122 N—H AS1 A0 C11 44 ESI: (M + H)⁺ = 0.1FM1 (KBr): C═O 790/2/4 (Br₂) 1624/1680 444 N122 N—H AS1 A0 C8 62 ESI:(M + H)⁺ = 0.18 FM1 (KBr): C═O 775/7/9 (Br₂) 1624/1678 445 N122 N—H AS1A0 C1 60 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 770/2/4 (Br₂) 1630/1680 446N122 N—H AS1 A0 C20 59 ESI: (M + H)⁺ = 0.15 FM1 (KBr): C═O 789/91/93(Br₂) 1622/1680 447 N122 N—H AS4 A0 C1 54 ESI: (M + H)⁺ = 0.6 FM1 (KBr):C═O 769/71/73 (Br₂) 1622/1682 448 N122 N—H AS4 A0 C20 68 ESI: (M + H)⁺ =0.5 FM1 (KBr): C═O 788/90/92 (Br₂) 1620/1682 449 N122 N—H AS4 A0 C8 59ESI: (M + H)⁺ = 0.58 FM1 (KBr): C═O 774/6/8 (Br₂) 1620/1682 450 N66N—CH₃ AS1 A0 C4 36 ESI: (M + H)⁺ = 0.39 FM1 (KBr): C═O 753/5/7 (Br₂)1653 451 N66 CH₂ AS1 A0 C1 20 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O739/41/43 (Br₂) 1638 452 N71 CH₂ AS1 A0 C1 16 ESI: (M + H)⁺ = 0.4 FM1(KBr): C═O 751/53/55 (Br₂) 1638/1680 453 N66 CH₂ AS1 A0 C11 17 ESI: (M +H)⁺ = 0.13 FM1 (KBr): C═O 758/60/62 (Br₂) 1636 454 N66 CH₂ AS1 A0 C20 33ESI: (M + H)⁺ = 0.23 FM1 (KBr): C═O 757/59/61 (Br₂) 1632 455 N71 CH₂ AS1A0 C8 35 EI: M⁺ = 0.42 FM1 (KBr): C═O 755/7/9 (Br₂) 1624/1684 457 N71CH₂ AS1 A0 C4 49 ESI: (M + H)⁺ = 0.77 FM1 (KBr): C═O 750/2/4 (Br₂)1626/1682 458 N71 CH₂ AS1 A0 C37 25 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O769/71/73 (Br₂) 1638/1682 459 N66 CH₂ AS1 A0 C37 50 EI: M⁺ = 0.2 FM1(KBr): C═O 757/59/61 (Br₂) 1636 460 N66 N—H AS1 A0 C55 72 ESI: (M + H)⁺= 0.27 EE/MeOH/ (KBr): C═O 759/61/63 (Br₂) NH₄OH = 1626/1661 8/1.5/0.1v/v/v 461 N66 N—H AS1 A0 C56 77 ESI: (M + H)⁺ = 0.77 FM1 (KBr): C═O731/3/5 (Br₂) 1626/1661 462 N66 N—H AS17 A0 C8 51 ESI: (M + H)⁺ = 0.44FM1 (KBr): C═O 759/61/63 (Br₂) 1628/1663 463 N66 N—H AS18 A0 C1 59 ESI:(M + H)⁺ = 0.7 FM1 (KBr): C═O 704 1661 464 N66 N—H AS18 A0 C8 51 ESI:(M + H)⁺ = 0.76 FM1 (KBr): C═O 709 1628/1663 465 N66 N—H AS18 A0 C37 73ESI: (M + H)⁺ = 0.7 FM1 (KBr): C═O 723 1628/1663 469 N66 N—H AS19 A0 C834 ESI: (M + H)⁺ = 0.34 FM1 (KBr): C═O 651/53 (Br) 1626/1664 471 N66 N—HAS20 A0 C8 41 ESI: (M + H)⁺ = 0.68 FM1 (KBr): C═O 649 1624/1684 472 N66N—H AS5 A0 C8 26 ESI: (M + H)⁺ = 0.73 FM1 (KBr): C═O 729/31/33 (Br₂)1626/1664 475 N66 N—H AS18 A0 C20 58 ESI: (M + H)⁺ = 0.22 FM1 (KBr): C═O723 1628/1664 476 N66 N—H AS18 A0 C11 44 ESI: (M + H)⁺ = 0.27 MeOH(KBr): C═O 724 1630/1662 478 N66 N—H AS19 A0 C37 62 ESI: (M + H)⁺ = 0.8FM1 (KBr): C═O 665/7 (Br) 1626/1662 479 N66 N—H AS19 A0 C20 55 ESI: (M +H)⁺ = 0.64 FM1 (KBr): C═O 665/7 (Br) 1664 480 N66 N—H AS19 A0 C4 55 ESI:(M + H)⁺ = 0.77 FM1 (KBr): C═O 645/7 (Br) 1628/1662 506 N66 N—H AS21 A0C20 46 ESI: (M + H)⁺ = 0.75 FM1 (KBr): C═O 655 1626/1664 507 N66 N—HAS22 A0 C8 65 ESI: (M + H)⁺ = 0.78 FM1 (KBr): C═O 607/9 (Cl) 1624/1664508 N66 CH₂ AS21 A0 C20 15 ESI: (M + H)⁺ = 0.15 MeOH (KBr): C═O 6541639/1670 246 N15 CH₂ AS1 A0 C8 19 ESI: (M + H)⁺ = 0.35 EE/MeOH/ (KBr):C═O 730/2/4 (Br₂) NH₄OH 1635/1707 9/1/0.5 v/v/v 285 N15 CH₂ AS1 A0 C4 42ESI: (M + H)⁺ = 0.45 EE/MeOH/ (KBr): C═O 724/6/8 (Br₂) NH₄OH 1684/17119/1/0.5 v/v/v 289 N66 CH₂ AS1 A0 C8 40 ESI: (M + H)⁺ = 0.38 EE/MeOH/(KBr): C═O 744/6/8 (Br₂) NH₄OH 1635/1668 9/1/0.5 v/v/v 290 N66 CH₂ AS1A0 C4 30 ESI: (M + H)⁺ = 0.45 EE/MeOH/ (KBr): C═O 738/40/42 (Br₂) NH₄OH1634/1664 9/1/0.5 v/v/v 511 N66 N—H AS23 A0 C8 DMF 80 ESI: (M + H)⁺ =0.57 FM1 (KBr): C═O 603 1664/1626 512 N66 N—H AS23 A0 C11 DMF 60 ESI:(M + H)⁺ = 0.30 FM1 (KBr): C═O 618 1645 513 N66 N—H AS23 A0 C1 DMF 54ESI: (M + H)⁺ = 0.50 FM1 (KBr): C═O 598 1662/1712 514 N66 N—H AS23 A0C38 DMF 65 ESI: (M + H)⁺ = 0.20 FM1 (KBr): C═O 644 1664/1626/1712 515N66 N—H AS23 A0 C40 DMF 7 ESI: (M + H)⁺ = 0.40 FM1 (KBr): C═O 6321630/1662 527 N66 N—H AS25 A0 C8 49 ESI: (M + H)⁺ = 0.48 FM1 (KBr): C═O594 1647 528 N66 N—H AS25 A0 C1 29 ESI: (M + H)⁺ = 0.48 FM1 (KBr): C═O589 1646 529 N66 CH₂ AS2 A0 C8 27 ESI: (M + H)⁺ = 0.50 FM1 (KBr): C═O622 1635/1668/1716 530 N66 CH₂ AS2 A0 C20 5 EI: M⁺ = 635 0.49 FM1 (KBr):C═O 1637/1668/1714 531 N66 CH₂ AS23 A0 C8 30 EI: M⁺ = 601 0.50 FM1 N66CH₂ AS23 95 538 N139 CH₂ AS2 A0 C20 49 EI: M⁺ = 636 0.30 FM1 (KBr): C═O1635/1674 539 N139 CH₂ AS2 A0 C53 52 EI: M⁺ = 637 0.30 FM1 (KBr): C═O1637/1674 540 N139 CH₂ AS2 A0 C8 60 0.37 FM1 (KBr): C═O 1635/1674 541N66 CH₂ AS27 A0 C53 32 EI: M⁺ = 630 0.65 FM1 (KBr): C═O 1639/1670 542N66 CH₂ AS27 A0 C8 32 EI: M⁺ = 615 0.80 FM1 (KBr): C═O 1639/1670 543 N66CH₂ AS27 A0 C20 21 EI: M⁺ = 629 0.59 FM1 (KBr): C═O 1639/1672 544 N66CH₂ AS28 A0 C20 35 EI: M⁺ = 643 0.50 FM1 (KBr): C═O 1641/1670 545 N66CH₂ AS28 A0 C53 54 EI: M⁺ = 644 0.50 FM1 (KBr): C═O 1639/1670 546 N66CH₂ AS28 A0 C8 53 EI: M⁺ = 629 0.60 FM1 (KBr): C═O 1639/1672 547 N66 CH₂AS29 A0 C8 14 EI: M⁺ = 599 0.53 FM1 (KBr): C═O 1630 548 N66 CH₂ AS29 A0C53 12 EI: M⁺ = 614 0.48 FM1 549 N66 CH₂ AS29 A0 C20 15 EI: M⁺ = 6130.48 FM1 (KBr): C═O 1637/1668 550 N66 CH₂ AS30 A0 C53 4 0.48 FM1 574 N66CH₂ AS16 A0 C20 55 EI: M⁺ = 0.80 CH₂Cl₂/MeOH/ (KBr): C═O 653/5/7 (Cl₂)NH4OH 80/20/1 1635/1670 575 N66 CH₂ AS16 A0 C53 54 EI: M⁺ = 0.20EE/MeOH/ (KBr): C═O 654/6/8 (Cl₂) NH₄OH 70/30/3 1635/1668 578 N66 CH₂AS5 A0 C53 32 EI: M⁺ = 0.30 FM5 (KBr): C═O 742/4/6 (Br₂) 1637/1670 579N66 CH₂ AS5 A0 C20 37 EI: M⁺ = 0.50 FM5 (KBr): C═O 741/3/5 (Br₂)1635/1670 589 N66 CH₂ AS32 A0 C53 49 EI: M⁺ = 0.33 FM5 (KBr): C═O756/58/60 (Br₂) 1639/1670 590 N66 CH₂ AS32 A0 C20 36 EI: M⁺ = 0.47 FM5(KBr): C═O 755/7/9 (Br₂) 1658/1672 591 N66 CH₂ AS33 A0 C20 43 EI: M⁺ =689 0.40 EE/MeOH/ (KBr): C═O NH₄OH 50/50/0.5 1637/1670 592 N66 CH₂ AS33A0 C53 52 EI: M⁺ = 690 0.20 EE/MeOH/ (KBr): C═O NH₄OH 70/30/5 1633/1668593 N66 CH₂ AS16 A0 C29 11 EI: M⁺ = 0.65 EE/MeOH (KBr): C═O 628/30/32(Cl₂) 9/1 1606/1637/ 1668/1728 594 N66 CH₂ AS16 A0 C73 48 EI: M⁺ = 0.50EE/MeOH (KBr): C═O 628/30/32 (Cl₂) 9/1 1637/1668/1736 595 N66 CH₂ AS16A0 C74 10 EI: M⁺ = 0.30 EE/MeOH 597/99/601 (Cl₂) NH₄OH 50/50/0.5 597 N66CH₂ AS31 A0 C53 25 EI: M⁺ = 639 0.30 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH90/10/1 1635/1668 598 N66 CH₂ AS31 A0 C20 31 EI: M⁺ = 638 0.10CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 90/10/0.3 1635/1668 600 N73 CH₂ AS31 A0C20 10 ESI: (M + H)⁺ = 0.15 CH₂Cl₂/MeOH/ (KBr): C═O 551 NH₄OH 90/10/11628 602 N66 CH₂ AS17 A0 C53 56 EI: M⁺ = 0.25 EE/MeOH/ (KBr): C═O772/4/6 (Br₂) NH₄OH 50/50/0.5 1637/1668 603 N66 CH₂ AS16 A0 C33 93 EI:M⁺ = 0.75 EE/MeOH/ (KBr): C═O 600/02/04 (Br₂) AcOH 70/30/1 1635/1716 604N66 CH₂ AS17 A0 C20 47 EI: M⁺ = 0.20 EE/MeOH/ (KBr): C═O 771/3/5 (Br₂)NH₄OH 50/50/0.5 1635/1668 605 N66 CH₂ AS34 A0 C53 70 EI: M⁺ = 672 0.25EE/MeOH/ (KBr): C═O NH₄OH 60/40/0.5 1633/1666 606 N66 CH₂ AS34 A0 C20 45EI: M⁺ = 671 0.15 EE/MeOH/ (KBr): C═O NH₄OH 50/50/0.5 1635/1668 607 N66N—H AS21 A0 C40 27 ESI: (M + H)⁺ = 0.65 FM1 (KBr): C═O 6701608/1628/1664 608 N66 N—H AS21 A0 C11 34 ESI: (M + H)⁺ = 0.50 FM1(KBr): C═O 656 1606/1628/1664 609 N66 N—H AS21 A0 C8 30 ESI: (M + H)⁺ =0.80 FM1 (KBr): C═O 641 1626/1664 610 N66 N—H AS21 A0 C1 55 ESI: (M +H)⁺ = 0.80 FM1 (KBr): C═O 636 1635/1662 611 N66 N—H AS21 A0 C4 80 ESI:(M + H)⁺ = 0.70 FM1 (KBr): C═O 635 1606/1628/1664 612 N66 CH₂ AS4 A0 C843 EI: M⁺ = 0.85 FM1 (KBr): C═O 742/4/6 (Br₂) 1668/1631/1606 613 N66 N—HAS22 A0 C20 62 ESI: (M + H)⁺ = 0.73 FM1 (KBr): C═O 621/23 (Cl) 1626/1664614 N66 N—H AS22 A0 C37 55 ESI: (M + H)⁺ = 0.68 FM1 (KBr): C═O 621/23(Cl) 1626/1664 615 N66 N—H AS22 A0 C56 77 ESI: (M + H)⁺ = 0.76 FM1(KBr): C═O 593 1628/1664 616 N66 CH₂ AS36 A0 C8 32 ESI: (M + H)⁺ = 0.76FM1 (KBr): C═O 585 1637/1668 617 N66 CH₂ AS21 A0 C37 15 EI: M⁺ = 6530.15 MeOH (KBr): C═O 1639/1670 618 N66 CH₂ AS21 A0 C38 24 EI: M⁺ = 6800.10 MeOH (KBr): C═O 1639/1670 628 N66 CH₂ AS21 A0 C8 31 EI: M⁺ = 6390.25 MeOH (KBr): C═O 1639/1670 629 N66 CH₂ AS21 A0 C11 43 EI: M⁺ = 6540.10 MeOH (KBr): C═O 1641/1668 630 N66 CH₂ AS21 A0 C1 74 EI: M⁺ = 6340.10 MeOH (KBr): C═O 1641/1668 631 N66 CH₂ AS21 A0 C28 63 EI: M⁺ = 6140.30 MeOH (KBr): C═O 1666 634 N66 CH₂ AS38 A0 C8 35 ESI: (M + H)⁺ = 0.25MeOH (KBr): C═O 622 1635/1668 635 N66 CH₂ AS48 A0 C8 40 EI: M⁺ = 6390.68 FM1 (KBr): C═O 1643/1670 636 N66 N—H AS49 A0 C20 25 ESI: (M + H)⁺ =0.40 EE/MeOH/ (KBr): C═O 632 NH₄OH 9/1/0.5 1664 637 N66 CH₂ AS4 A0 C2011 ESI: (M + H)⁺ = 0.60 FM1 (KBr): C═O 757/59/61 (Br₂) 1635/1668 638 N66CH₂ AS48 A0 C20 11 ESI: (M + H)⁺ = 0.66 FM1 (KBr): C═O 654 1641/1668 639N66 CH₂ AS18 A0 C20 4 EI: M⁺ = 721 0.10 MeOH (KBr): C═O 1637/1670 640N66 CH₂ AS39 A0 C20 38 EI: M⁺ = 645 0.80 CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH8/2/0.3 1635/1670 641 N66 CH₂ AS38 A0 C20 49 EI: M⁺ = 635 0.80CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 8/2/0.3 1635/1668 642 N66 CH₂ AS39 A0 C845 EI: M⁺ = 631 0.10 EE/MeOH/ (KBr): C═O NH₄OH 9/1/0.3 1635/1670 N66 CH₂AS21 A0 C69 70 EI: M⁺ = 739 (KBr): C═O 1684 644 N109 CH₂ AS21 A0 C20 46ESI: (M + H)⁺ = 0.10 MeOH (KBr): C═O 659 1643 645 N66 CH₂ AS19 A0 C20 21EI: M⁺ = 0.53 FM1 (KBr): C═O 763/5 (Br) 1669/1634 646 N66 CH₂ AS19 A0 C845 EI: M⁺ = 0.60 FM1 (KBr): C═O 649/651 (Br) 1637/1668 653 N113 CH₂ AS21A0 C20 55 EI: M⁺ = 666 0.60 FM1 (KBr): C═O 1630/1701 654 N134 CH₂ AS21A0 C20 22 EI: M⁺ = 690 0.60 FM1 (KBr): C═O 1714 655 N66 CH₂ AS46 A0 C2043 EI: M⁺ = 636 0.50 FM1 (KBr): C═O 1630/1664 656 N66 CH₂ AS46 A0 C8 71EI: M⁺ = 622 0.60 FM1 (KBr): C═O 1635 657 N66 CH₂ AS47 A0 C20 63 EI: M⁺= 639 0.50 FM1 (KBr): C═O 1635/1668/1716 658 N66 CH₂ AS50 A0 C20 70 ESI:(M + H)⁺ = 0.20 EE/MeOH/ (KBr): C═O 741/3/5 (Br₂) NH₄OH 50/50/0.51635/1668 659 N66 CH₂ AS50 A0 C53 60 ESI: (M + H)⁺ = 0.20 EE/MeOH/(KBr): C═O 743/5/7 (Br₂) NH₄OH 50/50/0.5 1635/1668 660 N66 CH₂ AS46 A0C53 41 EI: M⁺ =637 0.65 FM1 (KBr): C═O 1630 661 N66 CH₂ AS7 A0 C8 75 EI:M⁺ = 615 0.70 FM1 (KBr): C═O 1626/1660 662 N66 CH₂ AS7 A0 C53 41 EI: M⁺= 630 0.55 FM1 (KBr): C═O 1628/1662 663 N66 CH₂ AS7 A0 C20 78 EI: M⁺ =629 0.60 FM1 (KBr): C═O 1628/1662 664 N66 CH₂ AS52 A0 C8 66 EI: M⁺ = 6290.75 FM1 (KBr): C═O 1635 665 N66 CH₂ AS52 A0 C53 37 EI: M⁺ = 644 0.70FM1 (KBr): C═O 1633/1664 666 N66 CH₂ AS52 A0 C20 61 EI: M⁺ = 643 0.80FM1 (KBr): C═O 1635/1664 667 N66 CH₂ AS2 A0 C53 47 EI: M⁺ = 636 0.60 FM1(KBr): C═O 1630/1664 N66 CH₂ AS2 A0 C69 78 0.75 FM1 669 N66 CH₂ AS32 A0C71 44 EI: M⁺ = 0.20 EE/MeOH/ (KBr): C═O 834/6/8 (Br₂) NH₄OH 50/50/0.51641/1670 670 N66 CH₂ AS51 A0 C20 Preliminary 47 EI: M⁺ = 641 0.15EE/MeOH/ (KBr): C═O stage special NH₄OH 50/50/0.5 1635/1664 cases 671N66 CH₂ AS51 A0 C53 45 EI: M⁺ = 642 0.15 EE/MeOH/ (KBr): C═O NH₄OH50/50/0.5 1637/1670 672 N66 CH₂ AS16 A0 C76 55 EI: M⁺ = 0.66 FM1 (KBr):C═O 689/91/93 (Cl₂) 1635

EXAMPLE 2

Preparation of compounds of general formula:

1-[N²-[4-amino-N-[[4-(2-chlorophenyl)-1-piperazinyl]-carbonyl]-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)piperazine-bis-(trifluoroacetate)(No. 61)

A mixture of 0.56 g (1.0 mmol) of4-amino-N²-[[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-3.5-dibromo-D-phenylalanine,0.41 g (1.05 mmol) of1-[N⁶-(1.1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine,0.35 g (1.10 mmol) of TBTU, 0.14 g (1.0 mmol) of HOBt, 0.2 ml (1.10mmol) of DIEA and 100 ml of dimethylformamide was stirred overnight atambient temperature. The reaction mixture was evaporated down in vacuoand divided between methylene chloride and saturated aqueous sodiumhydrogen carbonate solution. The organic phase was then extracted oncewith saturated aqueous sodium hydrogen carbonate solution and withwater, dried and evaporated down in vacuo. The crude product waspurified by column chromatography (MN-silica gel 60, Macherey-Nagel,70-230 mesh ASTM, eluant: ethyl acetate/methanol=8/2 (v/v/)), taken upin 30 ml of methylene chloride and stirred with 3 ml of trifluoroaceticacid for 3 hours at ambient temperature. The reaction mixture wasevaporated down in vacuo, the residue was triturated with ether and theobtained amorphous solid (0.43 g, 37% of theory) was suction filtered.

IR (KBr): 1643, 1678 cm⁻¹ (C═O)

R_(f): 0.6 (FM1)

ESI-MS: (M+H)⁺=832/834/836/838 (Br₂,Cl)

The following were prepared analogously (in each case n=1):

No. RCO R² A NR³R⁴ % Yield MS R_(f) Eluant IR [cm⁻¹] 48 N6 AS1 A1 C3 79ESI: M + H = 0.3 FM1 (KBr): C═O 946/48/50 1652.9; 1674.1 (Br₂) 213  N15AS6 A1 C8 14.7 ESI: M + H = 0.45 FM2 (KBr): C═O 781/3 (Br) 1691.5;1629.8 49 N8 AS4 A1 C1 57.14 ESI: M + H = 0.5 FM1 (KBr):C═O 757/59/611643.3; 1676.0 (Br₂) 58 N15 AS4 A1 C4 21 ESI: M + H = 0.57 FM1 (KBr):C═O 852/4/6 (Br₂) 1635.5; 1695.3 59 N15 AS4 A1 C1 45.6 ESI: M + H = 0.44FM1 (KBr): C═O 853/5/7 (Br₂) 1635.5; 1695.3 60 N23 AS4 A1 C4 19.2 ESI:M + H = 0.65 FM1 (KBr): C═O 831/3/5/7 1633.6 (Br₂, Cl) 61 N23 AS4 A1 C136.6 ESI: M + H = 0.6 FM1 (KBr): C═O 832/4/6/8 1643.3; 1678.0 (Br₂, Cl)

EXAMPLE 3

Preparation of compounds of general formula:

1-[N²-[3,5-dibromo-N-[[[(2-methoxyphenyl)methyl]amino]-carbonyl]-D,L-tyrosyl]-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine

A tetrahydrofuran solution (50 ml) of 1.0 g (1.34 mmol) of1-[N²-(3,5-dibromo-D-tyrosyl)-N⁶-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazinewas added dropwise over a period of 40 minutes to a suspension of 0.33 g(2.01 mmol) of CDT in 50 ml of tetrahydrofuran cooled to −10 ° C. andstirred. The reaction mixture was then stirred for 2 hours at ambienttemperature and mixed with 0.22 ml (1.675 mmol) of2-methoxybenzenethanamine. Then the mixture was refluxed for 2 hours andstirred overnight at ambient temperature. The reaction mixture wasevaporated down in vacuo, the residue was triturated with ether and thesolid obtained (1.1 g; 90% of theory) was suction filtered and dried.

IR (KBr): 1641, 1717 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=908/910/912 (Br₂) (M+H+Na)⁺⁺=466.7 (Br₂)

The following were prepared analogously:

% Mp. No. RCO R² n X A NR³R⁴ Remarks Yield MS R_(f) Eluant IR [cm⁻¹] (°C.) 195 N15 AS1 1 O A3 C8 21 ESI: (M + H)⁺ = 0.8 FM7 (KBr): C═O959/61/63 1699.2 (Br₂) 1635.5 196 N51 AS1 1 O A3 C8 26.1 ESI: (M + H)⁺ =0.85 FM7 (KBr): C═O 929/31/33 1710; CN (Br₂) 2219.8 201 N101 AS4 1 O A0C8 DIEA 34 ESI: (M + H)⁺ = 0.58 FM1 (KBr): C═O 746/8/50 1693.4 (Br₂)1618.2 215 N15 AS1 1 O A0 C34 NEt₃ as 92 ESI: (M − H)⁻ = 0.36 FM1 (KBr):C═O base 778/80/82 1695.3 (Br₂) 216 N15 AS1 1 O A0 C35 NEt₃ as 69 ESI:(M − H)⁻ = 0.3 FM1 (KBr): C═O base 779/81/82 1701.1 (Br₂) 221 N15 AS4 1O A7 C1 NEt₃ as 39 ESI: (M + H)⁺ = 0.38 FM1 (KBr): C═O base 881/3/51697.3; (Br₂) 1637.5 288 N85 AS1 1 O A0 C8 THF/DMF 30 ESI: (M + H)⁺ =0.3 MeOH (KBr): C═O as solvent; 749/51/53 1683.8; NEt₃ as (Br₂) 1624.0base OH 3429.2 293 N66 AS1 1 O A9 C1 DIEA 11 ESI: (M + H)⁺ = 0.4 FM1(KBr): C═O 910/2/4 1645.2 (Br₂) 295 N66 AS1 1 O A7 C1 NEt₃ as 70 ESI:(M + H)⁺ = 0.45 FM1 (KBr): C═O base 896/8/900 1716.5 (Br₂) 1647.1 303N86 AS4 1 O A0 C8 DIEA 20 ESI: (M + H)⁺ = 0.7 FM 2 (KBr): C═O 747/9/511618.2 (Br₂) 304 N87 AS4 1 O A0 C8 THF as 30 ESI: (M + H)⁺ = 0.75 FM1(KBr): C═O solvent; 802/4/6 1720.4 NEt₃ as (Br₂) 1668.3; base 1620.1 NH,NH₂ 3431.2; 3379.1 305 N88 AS4 1 O A0 C8 DIEA 45 ESI: (M + H)⁺ = 0.6 FM1(KBr): C═O 782/4/6 1616; SO2 (Br₂) 1323.1 1151.4 308 N90 AS4 1 O A0 C8DIEA 27 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O 750/2/4 1637.5 (Br₂) 80 N15AS1 1 O A3 C1 62 ESI: (M + H)⁺ = 0.8 FM2 (KBr): C═O 954/6/8 1697.3;(Br₂) 1639.4 N8 AS1 1 O A3 C1 66 ESI: (M + H)⁺ = 0.22 EtOAc/ (KBr): C═O858/60/62 methanol = 1641.3 (Br₂) 6/4 (v/v) N9 AS1 1 O A3 C1 59 ESI:(M + H)⁺ = 0.22 EtOAc/ (KBr): C═O 888/90/92 methanol = 1652.9 (Br₂) 6/4(v/v) N2 AS1 1 O A4 C1 40 ESI: (M + H)⁺ = 0.45 FM1 (KBr): C═O 922/4/6(Br₂); 1641.3; (M + Na)⁺ = 1710.8; 944/6/8 (Br₂) OH, NH 3396.4 N4 AS1 1O A4 C1 73 ESI: (M + H)⁺ = 0.13 FM1 (KBr): C═O 952/4/6 (Br₂) 1641.3;1714.6 62 N15 AS1 1 O A3 C5 purified by 65 ESI: (M + H)⁺ = 0.27 FM1(KBR): C═O column 1003/5/7 (Br₂); 1685.7; chromato- (M + Na)⁺ = 1635.5;OH, graphy: silica 1025/7/9 (Br₂) NH: 3419.6 gel/FM4 N15 AS1 1 O A3 C6purified by 86 ESI: (M + H)⁺ = 0.45 FM1 (KBr): C═O column 983/5/7 (Br₂)1695.3, chromato- 1633.6 graphy: silica gel/FM4 73 N15 AS5 1 O A3 C1purified by 64 ESI: (M + H)⁺ = 0.75 FM1 (KBr): column 938/40/42 (Br₂)C═O 1699.2; chromato- 1641.3 graphy: silica gel/FM4; diastereo- mers 78N45 AS5 1 O A3 C1 purified by 44 ESI: (M + H)⁺ = 0.73 FM1 (KBr): C═Ocolumn 952/4/6 (Br₂) 1712.7, chromato- 1637.5; —NH— graphy: silica3300.0 gel/FM4; diastereo- mers 110 N15 AS4 1 O A0 C5 purified by 82ESI: (M + H)⁺ = 0.79 FM1 (KBr): C═O column 725/7/9 (Br₂) 1620.1;chromato- 1514.0 graphy: silica gel/FM4 111 N15 AS4 1 O A0 C15 purifiedby 58 ESI: M + = 0.77 FM1 (KBr): C═O column 726/28/30 (Br₂) 1697.3;chromato- 1620.1 graphy: silica gel/FM4 114 N45 AS4 1 O A0 C5 purifiedby 75 ESI: (M + H)⁺ = 0.78 FM1 (KBr): C═O column 739/41/43 (Br₂) 1710.8;chromato- 1620.1 graphy: silica gel/FM4 112 N15 AS1 1 O A0 C5 purifiedby 45 ESI: (M + H)⁺ = 0.33 FM1 (KBr): C═O column 726/28/30 (Br₂) 1695.3;chromato- 1624.0 graphy: silica gel/FM4 115 N45 AS1 1 O A0 C5 purifiedby 28 ESI: (M + H)⁺ = 0.35 FM1 (KBr): C═O column 740/2/4 (Br₂) 1710.8;chromato- 1622 graphy: silica gel/FM4 113 N15 AS4 1 O A0 C16 purified by56 ESI: (M + H)⁺ = 0.68 FM1 (KBr): C═O 173-176 column 726/8/30 (Br₂)1699.2; chromato- 1618.2 graphy: silica gel/FM4 119 N45 AS4 1 O A0 C16purified by 81 ESI: (M + H)⁺ = 0.69 FM1 (KBr): C═O 148-152 column762/4/6 (Br₂) 1710.8; chromato- 1618.2 graphy: silica gel/FM4 120 N15AS1 1 O A0 C15 purified by 27 ESI: (M + H)⁺ = 0.31 FM1 (KBr): C═O173-175 column 749/51/53 (Br₂) 1695.3 chromato- graphy: silica gel/FM4128 N15 AS4 1 O A0 C3 purified by 61 ESI: (M + Na)⁺ = 0.72 FM1 (KBr):C═O 174-177 column 764/6/8 (Br₂) 1699.2; chromato- 1618.2 graphy: silicagel/FM4 130 N15 AS4 1 O A0 C6 purified by 60 ESI: (M + H)⁺ = 0.7 FM1(KBr): C═O 150-154 column 754/6/8 (Br₂) 1703 chromato- 1620.1 graphy:silica gel/FM4 129 N15 AS1 1 O A0 C16 purified by 18 ESI: (M − H)⁻= 0.27FM1 (KBr): C═O 173-176 column 725/7/9 (Br₂) 1693.4; chromato- 1627.8graphy: silica gel/FM4 131 N45 AS4 1 O A0 C6 purified by 69 ESI: (M +H)⁺ = 0.73 FM1 (KBr): C═O 159-162 column 768/70/72 (Br₂) 1712.7;chromato- 1620.1 graphy: silica gel/FM4 132 N45 AS4 1 O A0 C3 purifiedby 27 ESI: (M + Na)⁺= 0.72 FM1 (KBr): C═O 142-146 column 778/80/2 (Br₂)1712.7; chromato- 1618.2 graphy: silica gel/FM4 133 N15 AS1 1 O A0 C6purified by 24 ESI: (M + H)⁺ = 0.33 FM1 (KBr): C═O 161-164 column755/7/9 (Br₂) 1697.3; chromato- 1624.0 graphy: silica gel/FM4 134 N15AS4 1 O A0 C18 purified by 69 ESI: (M + H)⁺ = 0.59 FM1 (KBr): C═O171-174 column 756/8/60 (Br₂) 1699.2; chromato- 1618.2 graphy: silicagel/FM4 135 N15 AS1 1 O A0 C18 Purified by 17 ESI: (M + H)⁺ = 0.25 FM1(KBr): C═O  74-77 column 757/9/61 (Br₂) 1691.5; 1625.9 chromato- graphy:silica gel/FM4 N29 AS1 1 O A3 C1 61 ESI: (M + H)⁺ = 0.62 FM7 (KBr): C═O903/5/7 (Br₂) 1641.3 N36 AS1 1 O A3 C1 33 ESI: (M + H)⁺ = 0.49 FM7(KBr): C═O 915/7/9 (Br₂) 1641.3 44 N34 AS1 1 O A3 C1 35 ESI: (M + H)⁺ =0.3 FM1 (KBr): C═O 936/38/40/42 1641.3 (Br₃) 378 N15 AS1 0 O A3 C1 30ESI: (M + H)⁺ = 0.13 FM1 (KBr): C═O 940/2/4 (Br₂) 1701.1; 1641.3 N48 AS11 O A3 C1 52 0.58 FM7 (KBr): C═O 1641.3 N77 AS1 1 O A3 C4 32 ESI: (M +H)⁺ = (KBr): C═O 955/7/9 (Br₂) 1645; 1713 294 N66 AS4 1 O A7 C1 NEt₃ asbase 31 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O 895/7/9 (Br₂) 1653; 1772.5;1716.5 323 N104 AS1 1 O A0 C4 DIEA 18 ES: (M + H)⁺ = 0.4 FM1 (KBr): C═O799/801/803 1624 (Br₂) 324 N105 AS1 1 O A0 C4 DIEA 24 ESI: (M + H)⁺ =0.38 FM1 (KBr): C═O 773/5/7/9 1624/1667 (Br₂/Cl) 325 N106 AS1 1 O A0 C4DIEA 22 ESI: (M + H)⁺ = 0.35 FM1 (KBr): C═O 725/7/9 (Br₂) 1626/1662.5326 N71 AS1 1 O A0 C1 DIEA 20 ESI: (M + H)⁺ = 0.16 FM1 (KBr): C═O752/4/6 (Br₂) 1624/1680 327 N71 AS4 1 O A0 C4 DIEA 24 ESI: (M + H)⁺ =0.48 FM1 (KBr): C═O 750/2/4 (Br₂) 1618/1682 328 N107 AS1 1 O A0 C4 DIEA17 ESI: (M + H)⁺ = 0.38 FM1 (KBr): C═O 769/71/73 (Br₂) 1651 329 N108 AS41 O A0 C4 DIEA 16 ESI: (M + H)⁺ = 0.31 FM1 (KBr): C═O 781/83/85 (Br₂)1620/1674 330 N108 AS4 1 O A0 C1 DIEA/DMF 15 ESI: (M + H)⁺ = 0.45 FM1(KBr): C═O 781/83/85 (Br₂) 1620/1678 331 N108 AS4 1 O A0 C20 DIEA/DMF 15ESI: (M + H)⁺ = 0.4 FM1 (KBr): C═O 800/802/804 1616/1680 (Br₂) 332 N109AS1 1 O A0 C4 DIEA/DMF 39 ESI: (M + H)⁺ = 0.32 FM1 (KBr): C═O 745/7/9(Br₂) 1665 333 N110 AS1 1 O A0 C4 DIEA/DMF 52 ESI: (M + H)⁺ = 0.34 FM1(KBr): C═O 745/7/9 (Br₂) 1636 334 N111 AS14 1 O A0 C1 DIEA/DMF 18 ESI:(M + H)⁺ = 0.5 FM1 (KBr): C═O 649 1626/1688 335 N109 AS4 1 O A0 C4DIEA/DMF 46 ESI: (M + H)⁺ = 0.47 FM1 (KBr): C═O 744/6/8 (Br₂) 1618 336N110 AS1 1 O A0 C8 DIEA/DMF 25 ESI: (M + H)⁺ = 0.22 FM1 (KBr): C═O751/3/5 (Br₂) 1645 337 N109 AS1 1 O A0 C8 DIEA/DMF 32 ESI: (M + H)⁺ =0.21 FM1 (KBr): C═O 751/3/5 (Br₂) 1645 338 N109 AS4 1 H2 A0 C8 DIEA/ 38ESI: (M + H)⁺ = 0.44 FM1 (KBr): C═O DMF 736/8/40 (Br₂) 1653 339 N110 AS41 H2 A0 C8 DIEA/ 39 ESI: (M + H)⁺ = 0.44 FM1 (KBr): C═O DMF 736/8/40(Br₂) 1653 340 N66 AS1 1 O A0 C20 DIEA/ 33 ESI: (M + H)⁺ = 0.12 FM1(KBr): C═O DMF 759/61/63 (Br₂) 1618/1657 341 N71 AS1 1 O A0 C20 DIEA/ 31ESI: (M + H)⁺ = 0.1 FM1 (KBr): C═O DMF 771/3/5 (Br₂) 1620/1680 342 N112AS4 1 O A0 C20 DIEA/ 27 ESI: (M + H)⁺ = 0.47 FM1 (KBr): C═O DMF 776/8/80(Br₂) 1618/1682 343 N112 AS1 1 O A0 C20 DIEA/ 26 ESI: (M + H)⁺ = 0.11FM1 (KBr): C═O DMF 777/9/81 (Br₂) 1624/1678 344 N71 AS1 1 O A0 C37 DIEA/52 ESI: (M + H)⁺ = 0.65 FM1 (KBr): C═O DMF 771/3/5 (Br₂) 1622/1680 345N66 AS1 1 O A0 C37 DIEA/ 50 ESI: (M + H)⁺ = 0.7 FM1 (KBr): C═O DMF759/61/63 (Br₂) 1626/1659 346 N71 AS4 1 O A0 C37 DIEA/ 37 ESI: (M + H)⁺= 0.75 FM1 (KBr): C═O DMF 770/72/74 (Br₂) 1620/1682 347 N6 AS4 1 O A0C37 DIEA/ 45 ESI: (M + H)⁺ = 0.8 FM1 (KBr): C═O DMF 758/60/62 (Br₂)1620/1663 348 N113 AS4 1 O A0 C20 DIEA/ 24 ESI: (M + H)⁺ = 0.8 FM1(KBr): C═O DMF 771/3/5 (Br₂) 1616/1701 349 N113 AS4 1 O A0 C8 DIEA/ 40ESI: (M + H)⁺ = 0.8 FM1 (KBr): C═O DMF 757/59/61 (Br₂) 1616/1699 350N111 AS4 1 O A0 C20 33 ESI: (M + H)⁺ = 0.63 FM1 (KBr): C═O 838/40/42(Br₂) 1620/1688 351 N111 AS4 1 O A0 C8 39 ESI: (M + H)⁺ = 0.64 FM1(KBr): C═O 824/6/8 (Br₂) 1620/1688 352 N111 AS1 1 O A0 C8 36 ESI: (M +H)⁺ = 0.37 FM1 (KBr): C═O 825/7/9 (Br₂) 1644/1688 353 N112 AS1 1 O A0 C824 ESI: (M + H)⁺ = 0.28 FM1 (KBr): C═O 763/5/7 (Br₂) 1624/1684 355 N113AS4 1 O A0 C11 DIEA/ 6 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O DMF 772/4/6(Br₂) 1620/1697 356 N66 AS4 1 O A0 C38 DIEA/ 31 ESI: (M + H)⁺ = 0.23 FM1(KBr): C═O DMF 785/7/9 (Br₂) 1624/1664 357 N112 AS4 1 O A0 C11 DIEA/ 5ESI: (M + H)⁺ = 0.37 FM1 DMF 777/79/81 (Br₂) 358 N111 AS1 1 O A0 C11DIEA/ 13 ESI: (M + H)⁺ = 0.09 FM1 (KBr): C═O DMF 840/42/44 (Br₂)1624/1686 359 N111 AS4 1 O A0 C11 DIEA/ 24 0.39 FM1 (KBr): C═O DMF1622/1686 360 N109 AS4 1 O A0 C8 DIEA/ 25 ESI: (M + H)⁺ = 0.7 FM1 (KBr):C═O DMF 750/52/54 (Br₂) 1618/1657 361 N110 AS4 1 O A0 C11 DIEA/ 35 ESI:(M + H)⁺ = 0.5 FM1 (KBr): C═O DMF 750/52/54 (Br₂) 1622/1649 362 N110 AS41 O A0 C8 DIEA/ 24 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O DMF 750/52/54(Br₂) 1649 363 N111 AS4 1 O A0 C37 DIEA/ 25 0.53 FM1 (KBr): C═O DMF1622/1688 364 N111 AS1 1 O A0 C37 DIEA/ 24 ESI: (M + H)⁺ = 0.3 FM1(KBr): C═O DMF 839/41/43 (Br₂) 1624/1686 366 N66 AS4 1 O A0 C39 67 ESI:(M + H)⁺ = 0.53 FM1 (KBr): C═O 772/4/6 (Br₂) 1618/1665 367 N71 AS4 1 OA0 C39 DIEA/ 12 ESI: (M + H)⁺ = 0.52 FM1 (KBr): C═O DMF 784/6/8 (Br₂)1618/1684 368 N111 AS4 1 O A0 C39 DIEA/ 37 ESI: (M + H)⁺ = 0.8 FM1(KBr): C═O DMF 852/4/6 (Br₂) 1618/1686 369 N114 AS4 1 O A0 C8 15 ESI:(M + H)⁺ = 0.58 FM1 (KBr): C═O 824/6/8 (Br₂) 1618/1686 370 N66 AS4 1 OA0 C40 DIEA/ 35 ESI: (M + H)⁺ = 0.44 FM1 (KBr): C═O DMF 773/5/7 (Br₂)1622/1660 371 N111 AS4 1 O A0 C40 DIEA/ 58 ESI: (M + H)⁺ = 0.44 FM1(KBr): C═O DMF 853/5/7 (Br₂) 1622/1687 373 N115 AS4 1 O A0 C8 DIEA/ 43ESI: (M + H)⁺ = 0.7 FM1 (KBr): C═O DMF 822/4/6/8 (Br₃) 1620/1670 374N116 AS4 1 O A0 C20 27 ESI: (M + H)⁺ = 0.53 FM1 (KBr): C═O 784/6/8 (Br)1618/1680 375 N117 AS4 1 O A0 C20 23 ESI: (M + H)⁺ = 0.52 FM1 (KBr): C═O815/7/9 (Br) 1620/1687 376 N118 AS4 1 O A0 C20 30 0.56 FM1 (KBr): C═O1620/1684 377 N119 AS4 1 O A0 C20 74 ESI: (M + H)⁺ = 0.61 FM1 (KBr): C═O848/50/52/54 1616/1685 (Br₃) 418 N111 AS4 1 O A0 C38 DIEA/ 23 ESI: (M +H)⁺ = 0.27 FM1 (KBr): C═O DMF 865/7/9 (Br) 1622/1687 490 N113 AS1 1 O A0C20 DIEA/ 37 ESI: (M + H)⁺ = 0.1 FM1 (KBr): C═O DMF 772/4/6 (Br₂)1622/1699 491 N113 AS1 1 O A0 C8 DIEA/ 94 ESI: (M + H)⁺ = 0.37 FM1(KBr): C═O DMF 758/60/62 (Br₂) 1624/1691 492 N113 AS1 1 O A0 C11 DIEA/42 ESI: (M + H)⁺ = 0.1 FM1 (KBr): C═O DMF 773/5/7 (Br₂) 1678 495 N133AS4 1 O A0 C20 45 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O 846/48/50 (Br₂)1620/1682 379 N71 AS1 1 O A0 C3 39 ESI: (M + H)⁺ = 0.41 FM4 (KBr): C═O769/71/73 (Br₂) 1680 380 N71 AS4 1 O A0 C3 40 ESI: (M + H)⁺ = 0.47 FM4(KBr): C═O 768/70/72 (Br₂) 1618/1682 381 N71 AS1 1 O A0 C42 11 ESI: (M +H)⁺ = 0.53 FM1 (KBr): C═O 752/54/56 (Br₂) 1624/1682 382 N66 AS1 1 O A0C42 18 ESI: (M + H)⁺ = 0.16 FM4 (KBr): C═O 740/42/44 (Br₂) 1630/1653 383N66 AS4 1 O A0 C42 47 ESI: (M + H)⁺ = 0.25 FM4 (KBr): C═O 739/41/43(Br₂) 1626/1659 384 N93 AS1 1 O A0 C1 11 ESI: (M + H)⁺ = 0.20 FM7 (KBr):C═O 790/92/94 (Br₂) 1636/1705 385 N71 AS4 1 O A0 C42 37 ESI: (M + H)⁺ =0.30 FM4 (KBr): C═O 751/53/55 (Br₂) 1620/1680 386 N71 AS4 1 O A0 C18 26ESI: (M + H)⁺ = 0.27 FM4 (KBr): C═O 782/4/6 (Br₂) 1620/1682 387 N66 AS41 O A0 C5 62 ESI: (M + H)⁺ = 0.38 FM4 (KBr): C═O 739/41/43 (Br₂)1626/1663 388 N71 AS4 1 O A0 C5 55 ESI: (M + H)⁺ = 0.39 FM4 (KBr): C═O751/3/5 (Br₂) 1618/1684 389 N66 AS1 1 O A0 C43 59 ESI: (M + H)⁺ = 0.32CH₂Cl₂/MeOH/ (KBr): C═O 796/98/800 NH₄OH 9/1/0.1 1653 (Br₂) 390 N135 AS41 O A0 C18 5 ESI: (M + H)⁺ = 0.71 FM1 (KBr): C═O 853/5/7 (Br₂) 1622/1653391 N135 AS1 1 O A0 C18 6 ESI: (M + H)⁺ = 0.54 FM1 (KBr): C═O 854/6/8(Br₂) 1659 392 N120 AS1 1 O A0 C4 12 ESI: (M + H)⁺ = 0.41 CH₂Cl₂/MeOH/(KBr): C═O 763/5/7 (Br₂) NH₄OH 9/1/0.1 1618/1639 393 N66 AS1 1 O A0 C4428 ESI: (M + H)⁺ = 0.50 CH₂Cl₂/MeOH/ (KBr): C═O 763/5/7 (Br₂) NH₄OH9/1/0.1 1659 394 N66 AS4 1 O A0 C21 37 ESI: (M + H)⁺ = 0.35 EE/MeOH/(KBr): C═O 740/42/44 (Br₂) AcOH 75/25/0.5 1659 396 N71 AS1 1 O A0 C21 49ESI: (M + H)⁺ = 0.30 EE/MeOH/ (KBr): C═O 753/5/7 (Br₂) AcOH 75/25/0.51622/1678 397 N66 AS1 1 O A0 C21 62 ESI: (M + H)⁺ = 0.35 EE/MeOH/ (KBr):C═O 741/3/5 (B₂) AcOH 75/25/0.5 1649 398 N121 AS4 1 O A0 C8 80 ESI: (M +H)⁺ = 0.55 CH₂Cl₂/MeOH/ (KBr): C═O 743/5/7 (Br₂) NH₄OH 9/1/0.1 1618/1668399 N122 AS4 1 O A0 C18 40 ESI: (M + H)⁺ = 0.62 FM1 (KBr): C═O 800/2/4(Br₂) 1622/1682 400 N136 AS4 1 O A0 C8 11 ESI: (M + H)⁺ = 0.65 FM1(KBr): C═O 741/3/5 (Br₂) 1622/1653 401 N66 AS1 1 O A0 C45 19 ESI: (M +H)⁺ = 0.65 CH₂Cl₂/MeOH/ (KBr): C═O 749/51/53 (Br₂) NH₄OH 9/1/0.1 1659402 N136 AS4 1 O A0 C1 10 ESI: (M + H)⁺ = 0.42 CH₂Cl₂/MeOH/ (KBr): C═O736/8/40 (Br₂) NH₄OH 9/1/0.1 1649 403 N121 AS4 1 O A0 C1 25 ESI: (M +H)⁺ = 0.43 CH₂Cl₂/MeOH/ (KBr): C═O 738/40/42 (Br₂) NH₄OH 9/1/0.11626/1676 404 N66 AS4 1 O A0 C46 58 ESI: (M + H)⁺ = 0.29 CH₂Cl₂/MeOH/(KBr): C═O 766/8/70 (Br₂₎ NH₄OH 9/1/0.1 1624/1663 405 N66 AS1 1 O A0 C4740 ESI: (M − H) = 0.3 EE/MeOH 9/1 (KBr): C═O 752/4/6 (Br₂) 1659 406 N136AS1 1 O A0 C1 16 ESI: (M + H)⁺ = 0.34 FM7 (KBr): C═O 737/39/41 (Br₂)1645 407 N121 AS1 1 O A0 C1 15 ESI: (M + H)⁺ = 0.36 FM7 (KBr): C═O739/41/43 (Br₂) 1638 408 N71 AS4 1 O A0 C48 47 ESI: (M + H)⁺ = 0.17CH₂Cl₂/MeOH/ (KBr): C═O 792/4/6 (Br₂) NH₄OH 9/1/0.1 1620/1680 409 N66AS4 1 O A0 C48 31 ESI: (M + H)⁺ = 0.43 CH₂Cl₂/MeOH/ (KBr): C═O 780/2/4(Br₂) NH₄OH 9/1/0.1 1665/1736 410 N66 AS1 1 O A0 C49 51 0.24 EE/MeOH 9/1(KBr): C═O 1661 411 N71 AS4 1 O A0 C44 45 ESI: (M + Na)⁺ = 0.35 EE/MeOH9/1 (KBr): C═O 796/98/800 1728 (Br₂) 412 N66 AS1 1 O A0 C50 58 ESI: (M +H)⁺ = 0.47 EE/MeOH 9/1 (KBr): C═O 756/58/60 (Br₂) 1642/1661 413 N66 AS11 O A0 C51 16 ESI: (M + H)⁺ = 0.47 EE/MeOH/ (KBr): C═O 788/90/92 (Br₂)NH₄OH 5/5/0.1 1631 414 N66 AS4 1 O A0 C52 34 ESI: (M + H)⁺ = 0.54 FM1(KBr): C═O 747/49/51 (Br₂) 1622/1662 415 N71 AS4 1 O A0 C52 35 ESI: (M +H)⁺ = 0.52 FM1 (KBr): C═O 759/61/63 (Br₂) 1620/1682 416 N66 AS4 1 O A0C53 53 ESI: (M + H)⁺ = 0.45 CH₂Cl₂/MeOH/ (KBr): C═O 759/61/63 (Br₂)NH₄OH 9/1/0.1 1620/1664 417 N71 AS4 1 O A0 C53 39 ESI: (M + H)⁺ = 0.43(KBr): C═O 771/3/5 (Br₂) 1620/1684 496 N66 AS4 1 O A0 C64 57 0.5CH₂Cl₂/MeOH/ (KBr): C═O NH₄OH 9/1/0.1 1635 497 N66 AS1 1 O A0 C53 60ESI: (M + H)⁺ = 0.31 CH₂Cl₂/MeOH/ (KBr): C═O 760/2/4 (Br₂) NH₄OH 167650/50/0.5 498 N66 AS4 1 O A0 C65 60 ESI: (M + H)⁺ = 0.39 FM1 (KBr): C═O760/2/4 (Br₂) 1676 499 N71 AS4 1 O A0 C65 53 ESI: (M + H)⁺ = 0.39 FM1(KBr): C═O 785/7/9 (Br₂) 1618/1684 500 N66 AS4 1 O A0 C51 71 ESI: (M +H)⁺ = 0.15 CH₂Cl₂/MeOH/ (KBr): C═O 787/89/91 (Br₂) NH₄OH 9/1/0.1 1628501 N71 AS1 1 O A0 C53 71 ESI: (M + H)⁺ = 0.25 CH₂Cl₂/MeOH/ (KBr): C═O772/4/6 (Br₂) NH₄OH 1676 50/50/0.5 502 N66 AS1 1 O A0 C65 42 ESI: (M +H)⁺ = 0.15 FM1 (KBr): C═O 774/6/8 (Br₂) 1626/1657 503 N71 AS1 1 O A0 C6548 ESI: M + H)⁺ = 0.12 FM1 (KBr): C═O 786/88/90 (Br₂) 1620/1682 504 N66AS4 1 O A0 C66 67 ESI: (M + H)⁺ = 0.65 CH₂Cl₂/MeOH/ (KBr): C═O 787/89/91(Br₂) NH₄OH 1624 50/50/0.5 297 N71 AS4 1 H2 A0 C8 9 ESI: (M + H)⁺ = 0.2FM1 (KBr): C═O 742/4/6 (Br₂) 1684 298 N71 AS13 1 H2 A0 C8 6 ESI: (M +H)⁺ = 0.16 FM1 (KBr): C═O 664/6 (Br) 1622/1682 299 N66 AS4 1 H2 A0 C8 21ESI: (M + H)⁺ = 0.25 FM1 (KBr): C═O 730/2/4 (Br₂) 1666 300 N66 AS13 1 H2A0 C8 14 ESI: (M + H)⁺ = 0.19 FM1 (KBr): C═O 652/4 (Br) 1666 301 N71 AS11 H2 A0 C8 26 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 743/5/7 (Br₂) 1682 420N87 AS1 1 O A0 C4 45 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O 797/99/8011624/1665/ (Br₂) 1719 422 N87 AS1 1 O A0 C8 35 ESI: (M + H)⁺ = 9.54 FM1(KBr): C═O 805/7/9 (Br₂) 1628/1668/ 1720 431 N125 AS4 1 O A0 C8 89 ESI:(M + H)⁺ = 0.75 FM1 (KBr): C═O 772/4/6 (Br₂) 1713/1773 432 N125 AS1 1 OA0 C4 59 ESI: (M + H)⁺ = 0.65 FM1 (KBr): C═O 767/69/71 (Br₂) 1622/1711/1773 433 N126 AS4 1 O A0 C4 33 ESI: (M + H)⁺ = 0.65 FM1 (KBr): C═O780/2/4 (Br₂) 1709/1769 434 N126 AS1 1 O A0 C8 53 ESI: (M + H)⁺ = 0.53FM1 (KBr): C═O 787/89/91 (Br₂) 1626/1707 440 N127 AS4 1 O A0 C8 67 ESI:(M + H)⁺ = 0.67 FM1 (KBr): C═O 780/2/4 (Br₂) 1618 441 N127 AS4 1 O A0C20 89 ESI: (M + H)⁺ = 0.24 EE/MeOH/ (KBr): C═O 794/6/8 (Br₂) NH₄OH 16188/1.5/0.3 442 N127 AS4 1 O A0 C4 83 ESI: (M + H)⁺ = 0.37 EE/MeOH/ (KBr):C═O 774/6/8 (Br₂) NH₄OH 1616/1732 8/1.5/0.3 456 N66 AS16 1 O A0 C8 83ESI: (M + H)⁺ = 0.32 EE/MeOH/ (KBr): C═O 641/3/5 (Cl₂) NH₄OH 1624/16658/1.5/0.1 466 N128 AS4 1 O A0 C8 13 ESI: (M + H)⁺ = 0.63 FM1 (KBr): C═O832/4/6 (Br₂) 1684 467 N129 AS4 1 O A0 C8 16 ESI: (M + H)⁺ = 0.63 FM1(KBr): C═O 806/08/10 (Br₂) 1618/1682 468 N129 AS1 1 O A0 C8 28 ESI: (M +H)⁺ = 0.29 FM1 (KBr): C═O 807/09/11 (Br₂) 1630/1680 470 N128 AS1 1 O A0C8 81 ESI: (M + H)⁺ = 0.63 FM1 (KBr): C═O 835/7/9 (Br₂) 1684 473 N130AS1 1 O A0 C8 40 ESI: (M + H)⁺ = 0.51 FM1 (KBr): C═O 787/89/91 (Br₂)1624/1678 474 N130 AS4 1 O A0 C8 17 ESI: (M + H)⁺ = 0.71 FM1 (KBr): C═O786/88/90 (Br₂) 1618/1684 477 N66 AS16 1 O A0 C1 33 ESI: (M + H)⁺ = 0.53EE/MeOH/ (KBr): C═O 636/38/40 (Cl₂) NH₄OH 9/1/1 1661 (v/v/v) 481 N131AS4 1 O A0 C37 30 ESI: (M + H)⁺ = 0.15 CH₂Cl₂/ (KBr): C═O 838/40/42/44MeOH 7/3 1618/1685 (Br₂; Cl₂) (v/v) 482 N131 AS4 1 O A0 C20 24 ESI: (M +H)⁺ = 0.15 CH₂Cl₂/ (KBr): C═O 838/40/42/44 MeOH 7/3 1618/1685 (Br₂; Cl₂)(v/v) 483 N132 AS4 1 O A0 C20 62 ESI: (M + H)⁺ = 0.55 FM1 (KBr): C═O804/6/8/10 1684 (Br₂; Cl) 484 N132 AS4 1 O A0 C37 85 ESI: (M + H)⁺ =0.60 FM1 (KBr): C═O 804/6/8/10 1616/1686 (Br₂; Cl) 505 N134 AS4 1 O A0C8 81 ESI: (M + H)⁺ = 0.74 FM1 (KBr): C═O 781/3/5 (Br₂) 1616/1714 292N66 AS1 1 H2 A0 C8 6 ESI: (M + H)⁺ = 0.25 FM1 (KBr): C═O 731/3/5 (Br₂)1607/1664 245 N72 AS4 1 H2 A0 C8 19 ESI: (M + H)⁺ = 0.30 FM1 (KBr): C═O731/3/5 (Br₂) 1668 220 N15 AS1 1 H2 A0 C8 6 ESI: (M + H)⁺ = 0.30 FM1(KBr): C═O 717/19/21 (Br₂) 1697.3 307 N87 AS4 1 O A0 C4 27 ESI: (M + H)⁺= 0.50 FM1 (KBr): C═O 796/98/800 1618/1670/ (Br₂) 1718 178 N74 AS1 1 OA0 C4 33 ESI: (M + H)⁺ = 0.60 EE/MeOH/ (KBr): C═O 679/81/83 (Br₂) AcOH1624 50/50/1 (v/v/v) 395 N71 AS4 1 O A0 C21 22 ESI: (M + H)⁺ = 0.25EE/MeOH/ 752/4/6 (Br₂) AcOH 50/25/0.5 (v/v/v) 509 N119 AS4 1 O A0 C38DMF 45 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 875/7/9/81 1687/1618 (Br₃) 510N118 AS4 1 O A0 C38 DMF 34 ESI: (M + H)⁺ = 0.4 FM1 (KBr): C═O 827/29/31(Br₂) 1682/1620 519 N137 AS4 1 O A0 C20 THF/ 62 ESI: (M + H)⁺ = 0.1 FM1(KBr): C═O DMF 786/88/90 (Br₂) 1618/1678 520 N138 AS4 1 O A0 C20 THF/DMF31 ESI: (M + H)⁺ = 0.45 FM1 (KBr): C═O 906/08/10 1693 (Br₂) N66 AS4 1 OA0 C69 DMF 100 533 N139 AS1 1 O A0 C8 44 ESI: (M + H)⁺ = 0.1 FM5 (KBr):C═O 746/48/50 1628 (Br₂) 534 N139 AS4 1 O A0 C20 60 ESI: (M + H)⁺ = 0.2FM5 (KBr): C═O 759/61/63 1618/1672 (Br₂) 535 N139 AS1 1 O A0 C53 34 ESI:(M + H)⁺ = 0.1 FM5 (KBr): C═O 761/63/65 1624/1670 (Br₂) 536 N140 AS4 1 OA0 C8 40 ESI: (M + H)⁺ = 0.37 FM1 (KBr): C═O 745/7/9 1616/1676 (Br₂) 537N140 AS1 1 O A0 C8 33.4 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O 746/48/501614/1672 (Br₂) 551 N66 AS1 1 O A0 C66 41 ESI: (M + H)⁺ = 0.3 EE/MeOH/(KBr): C═O 788/90/92 NH₄OH 1628 (Br₂) 50/50/0.5 552 N66 AS4 1 O A0 C7883 ESI: (M + H)⁺ = 0.6 CH₂Cl₂/MeOH/ (KBr): C═O 787/89/91 NH₄OH 1620(Br₂) 80/20/1 553 N66 AS1 1 O A0 C78 30 ESI: (M + H)⁺ = 0.5 CH₂Cl₂/MeOH/ (KBr): C═O 788/90/92 NH₄OH 1626 (Br₂) 80/20/1 554 N71 AS4 1 O A0C78 67 ESI: (M + H)⁺ = 0.5 CH₂Cl₂/MeOH/ (KBr): C═O 799/801/803 NH₄OH1622/1684 (Br₂) 80/20/1 555 N71 AS1 1 O A0 C78 26 ESI: (M + H)⁺ = 0.5CH₂Cl₂/MeOH/ (KBr): C═O 800/02/04 NH₄OH 1624/1684 (Br₂) 80/20/1 556 N66AS4 1 O A0 C70 71 ESI: (M + H)⁺ = 0.6 CH₂Cl₂/MeOH/ (KBr): C═O 788/90/92NH₄OH 1653 (Br₂) 50/50/0.5 557 N71 AS4 1 O A0 C70 27 ESI: (M + H)⁺ = 0.8CH₂Cl₂/MeOH/ 800/02/04 NH₄OH (Br₂) 50/50/0.5 558 N66 AS1 1 O A0 C64 61ESI: (M + H)⁺ = 0.3 CH₂Cl₂/MeOH/ (KBr): C═O 790/92/94 NH₄OH 1635 (Br₂)90/10/1 559 N141 AS4 1 O A0 C20 80 ESI: (M + H)⁺ = 0.3 CH₂Cl₂/MeOH/(KBr): C═O 626/28/30 NH₄OH 1618/1714 (Br₂) 90/10/1 560 N66 AS4 1 O A0C71 59 ESI: (M + H)⁺ = 0.3 CH₂Cl₂/MeOH/ (KBr): C═O 837/39/41 NH₄OH1628/62 (Br₂) 90/10/1 561 N71 AS4 1 O A0 C71 56 ESI: (M + H)⁺ = 0.2CH₂Cl₂/ (KBr): C═O 849/51/53 (Br₂) MeOH/ 1618/1684 NH₄OH 90/10/1 562 N66AS1 1 O A0 C70 15 ESI: (M + H)⁺ = 0.6 CH₂Cl₂/ (KBr): C═O 789/91/93 (Br₂)MeOH/ 1676 NH₄OH 50/50/0.5 563 N71 AS1 1 O A0 C70 27 ESI: (M + H)⁺ = 0.6CH₂Cl₂/ (KBr): C═O 80/3/5 (Br₂) MeOH/ 1678 NH₄OH 70/30/1 565 N66 AS4 1 OA0 C72 51 ESI: (M + H)⁺ = 0.2 CH₂Cl₂/ (KBr): C═O 787/89/91 (Br₂) MeOH/1622/1658 NH₄OH 80/20/1 566 N71 AS4 1 O A0 C72 65 ESI: (M + H)⁺ = 0.2CH₂Cl₂/ (KBr): C═O 799/801/803 MeOH/ 1620/1682 (Br₂) NH₄OH 80/20/1 567N136 AS4 1 O A0 C53 65 ESI: (M + H)⁺ = 0.5 CH₂Cl₂/ (KBr): C═O 756/58/60(Br₂) MeOH/ 1641 NH₄OH 80/20/1 568 N136 AS4 1 O A0 C72 76 ESI: (M + H)⁺= 0.2 CH₂Cl₂/ (KBr): C═O 784/6/8 (Br₂) MeOH/ 1637 NH₄OH 80/20/1 569 N136AS1 1 O A0 C53 63 ESI: (M + H)⁺ = 0.4 CH₂Cl₂/ (KBr): C═O 757/59/61 (Br₂)MeOH/ 1643 NH₄OH 80/20/1 570 N66 AS31 1 O A0 C20 85 ESI: (M + H)⁺ = 0.6CH₂Cl₂/ (KBr): C═O 640 MeOH/ 1622/1664 NH₄OH 80/20/1 571 N66 AS31 1 O A0C53 82 ESI: (M + H)⁺ = 0.8 CH₂Cl₂/ (KBr): C═O 641 MeOH/ 1664 NH₄OH80/20/1 572 N71 AS31 1 O A0 C20 100 ESI: (M + H)⁺ = 0.4 CH₂Cl₂/ (KBr):C═O 652 MeOH/ 1620/1684 NH₄OH 80/20/1 573 N71 AS31 1 O A0 C53 48 ESI:(M + H)⁺ = 0.4 CH₂Cl₂/ (KBr): C═O 653 MeOH/ 1622/1684 NH₄OH 80/20/1 576N66 AS11 1 O A0 C53 35 ESI: (M + H)⁺ = 0.65 CH₂Cl₂/ (KBr): C═O 727 MeOH/1664/1732 NH₄OH 80/20/1 577 N71 AS11 1 O A0 C53 73 ESI: (M + H)⁺ = 0.18EE/ (KBr): C═O 739 MeOH/ 1684/1734 NH₄OH 50/50/0.5 580 N66 AS11 1 O A0C20 65 ESI: (M + H)⁺ = 0.5 CH₂Cl₂/ (KBr): C═O 706 MeOH/ 1664/1732 NH₄OH80/20/1 581 N71 AS11 1 O A0 C20 38 ESI: (M + H)⁺ = 0.2 CH₂Cl₂/ (KBr):C═O 738 MeOH/ 1684/1734 NH₄OH 90/10/1 582 N143 AS4 1 O A0 C20 61 ESI:(M + H)⁺ = 0.5 CH₂Cl₂/ (KBr): C═O 758/60/62 MeOH/ 1615 NH₄OH 90/10/1 583N66 AS31 1 O A0 C72 50 ESI: (M + H)⁺ = 0.35 FM1 (KBr): C═O 669 1664 584N71 AS31 1 O A0 C72 68 ESI: (M + H)⁺ = 0.35 FM1 (KBr): C═O 681 1622/1684585 N144 AS4 1 O A0 C8 50 ESI: (M + H)⁺ = 0.43 FM5 (KBr): C═O927/29/31/33 1616/1684 (Br₄) 586 N144 AS4 1 O A0 C53 85 ESI: (M + H)⁺ =0.67 FM1 (KBr): C═O 942/4/6/8 (Br₄) 1680 587 N66 AS11 1 O A0 C72 37 ESI:(M + H)⁺ = 0.35 FM1 (KBr): C═O 755 1622/1658/ 1732 588 N71 AS11 1 O A0C72 81 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O 767 1684/1732 619 N71 AS19 1 OA0 C8 27.9 0.3 EE/MeOH/ (KBr): C═O NH₄OH 1622/1684 9/1/0.3 620 N66 AS351 O A0 C8 36 ESI: (M − H)⁻ = 0.25 MeOH (KBr): C═O 598 1628/1664 621 N66AS36 1 O A0 C8 32 ESI: (M − H)⁻ = 0.56 FM1 (KBr): C═O 587 1626/1666 622N71 AS36 1 O A0 C8 32 ESI: (M − H)⁻ = 0.44 FM1 (KBr): C═O 599 1622/1684623 N109 AS36 1 O A0 C8 37 ESI: (M − H)⁻ = 0.6 FM1 (KBr): C═O 5931626/1649 624 N118 AS36 1 O A0 C8 55 ESI: (M − H)⁻ = 0.6 FM1 (KBr): C═O629 1622/1684 625 N111 AS36 1 O A0 C8 47 ESI: (M − H)⁻ = 0.61 FM1 (KBr):C═O 667 1624/1687 626 N111 AS19 1 O A0 C8 20 ESI: (M − H)⁻ = 0.28EE/MeOH/ (KBr): C═O 731/3 (Br) NH₄OH 1624/1687 9/1/0.3 627 N109 AS19 1 OA0 C8 16 ESI: (M − H)⁻ = 0.28 EE/MeOH/ (KBr): C═O 657/9 (Br) NH₄OH 16539/1/0.3 633 N118 AS19 1 O A0 C8 20 ESI: (M + H)⁺ = 0.18 EE/MeOH/ (KBr):C═O 693/5 (Br) NH₄OH 1622/1684 9/1/0.3 N66 AS1 1 O A0 C69 100 0.3 FM4(KBr): C═O 1668

EXAMPLE 4

Preparation of compounds of general formula:

1-[4-amino-3,5-dibromo-N-[4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine(No. 91)

A mixture of 0.35 g (2.1 mmol) of CDT, 1.0 g (1.4 mmol) of4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-piperidine,0.5 ml of (2.8 mmol) of DIEA and 100 ml of tetra-hydrofuran was stirredfor 1 hour whilst cooling with ice and then for 30 minutes at ambienttemperature. With stirring 0.46 g (1.75 mmol) of1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyridinyl)piperazine and0.32 ml of (1.8 mmol) of DIEA were added and refluxed for 3 hours. Thereaction mixture was diluted with 100 ml of ethyl acetate and theorganic phase was washed twice with aqueous saturated sodium hydrogencarbonate solution. The combined aqueous phases were then extracted oncewith ethyl acetate/tetrahydrofuran=1/1 (v/v) and the combined organicphases were washed once with saturated aqueous saline solution. Afterdrying the organic phase and eliminating the solvent in vacuo theresidue was purified by column chromatography (MN-silica gel 60,Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=9/1(v/v)). 120 mg (12% of theory) of a colourless foam were obtained.

IR (KBr): 1626. 1686 cm⁻¹ (C═O)

R_(f): 0.62 (FM3)

ESI-MS: (M+H)⁺=731/733/735 (Br₂) (M+H+Na)⁺⁺=377/378/379 (Br₂)

The following were prepared analogously (in each case n=1):

% M.p. No. RCO R² A NR³R⁴ n Remarks Yield MS R_(f) Eluant IR [cm⁻¹] (°C.) N16 AS1 A3 C1 1 NEt₃ as base 31 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O974/6/8 (Br₂) 1641.3; 1695.3 86 N53 AS4 A0 C1 1 DMF as solvent 23 ESI:(M + H)⁺ = 0.5 FM1 (KBr): C═O 739/41/43 (Br₂) 1641.3; 1697.3 87 N54 AS4A0 C1 1 DMF als 81 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O Lösemittel739/41/43 (Br₂) 1620.1; 1697.3 92 N57 AS4 A0 C1 1 DMF as solvent 60 ESI:(M + H)⁺ = 0.6 FM1 (KBr): C═O 712/4/6 (Br₂) 1597; 1635.5 93 N47 AS4 A0C1 1 23 ESI: (M + H)⁺ = 0.4 FM1 (KBr): C═O 636/8/40 (Br₂) 1622; 1675 94N45 AS4 A0 C1 1 45 ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O 739/41/43 (Br₂)1598.9; 1620.1 95 N57 AS1 A0 C1 1 DMF as solvent 13 ESI: (M + H)⁺ = 0.2FM1 (KBr): C═O 713/5/7 (Br₂) 1637.5 96 N53 AS1 A0 C1 1 DMF as solvent 15ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 740/2/4 (Br₂) 1633.6; 1687.6 97 N54AS1 A0 C1 1 DMF as solvent 31 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 740/2/4(Br₂) 1635.5; 1695.3 107 N59 AS4 A0 C1 1 76 ESI: (M + H)⁺ = 0.7 FM1(KBr): C═O 694/6/8 (Br₂) 1597; 1635.5 108 N45 AS1 A0 C1 1 37 ESI: (M +H)⁺ = 0.3 FM1 (KBr): C═O 740/2/4 (Br₂) 1633.6; 1708.8 109 N59 AS1 A0 C11 30 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O 695/7/9 (Br₂) 1647.4 116 N60 AS4A0 C1 1 DMF as solvent 80 ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O 753/5/7(Br₂) 1623.7; 1676.1; 1712.7 117 N60 AS1 A0 C1 1 DMF as solvent 50 ESI:(M + H)⁺ = 0.4 FM1 (KBr): C═O 754/6/8 (Br₂) 1617; 1650; 1670; 1712.7 118N47 AS1 A0 C1 1 29 ESI: (M + H)⁺ = 0.1 FM1 (KBr): C═O 637/9/41 (Br₂)1639.4 121 N61 AS1 A0 C1 1 12.4 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O727/9/31 (Br₂) 1635.5; 1705 122 N61 AS4 A0 C1 1 42 ESI: (M + H)⁺ = 0.6FM1 (KBr): C═O 726/8/30 (Br₂) 1620.1; 1706.9 125 N15 AS7 A0 C1 1 NEt₃ asbase 4.4 ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O 598 1708.8 126 N15 AS7 A0 C41 NEt₃ as base 57 ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O 188.0 597 1622;1708.8 127 N15 AS7 A0 C8 1 NEt₃ as 16 ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O168- base 603 1622; 170 1697.3 137 N94 AS4 A0 C4 1 42 ESI: (M + H)⁺ =0.8 FM1 (KBr): C═O 708/10/12 (Br₂) 1618 138 N95 AS4 A0 C8 1 NEt₃ as 29ESI: (M + H)⁺ = 0.8 FM1 (KBr): C═O base 743/5/7 (Br₂) 1713 139 N61 AS1A3 C1 1 41 ESI: (M + H)⁺ = 0.4 FM1 (KBr): C═O 955/7/9 (Br₂) 1640; 1709140 N60 AS1 A3 C1 1 66 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O 982/4/6 (Br₂)1645; 1712 143 N66 AS1 A0 C4 1 DMF as 69 ESI: (M + H)⁺ = 0.4 FM1 (KBr):C═O solvent 739/41/43 (Br₂) 1624; 1659 144 N96 AS1 A0 C4 1 54 ESI: (M +H)⁺ = 0.54 FM1 (KBr): C═O 725/7/9 (Br₂) 1616 145 N61 AS1 A0 C4 1 48 ESI:(M + H)⁺ = 0.6 FM1 (KBr): C═O 724/6/8 (Br₂) 1624; 1709 146 N15 AS14 A0C1 1 DMF as 53 ESI: (M + H)⁺ = 0.15 FM1 (KBr): C═O solvent 555 1636;1701 147 N61 AS4 A0 C11 1 30 ESI: (M + H)⁺ = 0.7 FM1 (KBr): C═O746/48/50 (Br₂) 1620; 1713 148 N66 AS1 A0 C8 1 THF/DMF 58 ESI: (M + H)⁺= 0.68 FM1 (KBr): C═O as solvent 745/7/9 (Br₂) 1628; 1663 149 N69 AS1 A0C4 1 THF/DMF 61 ESI: (M + H)⁺ = 0.68 FM1 (KBr): C═O as solvent 739/41/43(Br₂) 1624; 1675 150 N97 AS1 A0 C4 1 THF/DMSO 32 ESI: (M + H)⁺ = 0.4 FM1(KBr): C═O as solvent 783/85/87 (Br₂) 1709 152 N71 AS1 A0 C4 1 40 ESI:(M + H)⁺ = 0.68 FM1 (KBr): C═O 751/53/55 (Br₂) 1622; 1684 153 N65 AS1 A0C4 1 51 ESI: (M + H)⁺ = 0.68 FM1 (KBr): C═O 751/53/55 (Br₂) 1626; 1678N66 AS1 A3 C1 1 37 225 N66 AS1 A0 C1 1 THF/DMF 48 ESI: (M + H)⁺ = 0.35FM1 (KBr): C═O as solvent 740/42/44 (Br₂) 1650; 1670 226 N66 AS4 A0 C8 1THF/DMF 88 ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O as solvent 744/6/8 (Br₂)1618; 1661 227 N69 AS4 A0 C8 1 THF/DMF 72 ESI: (M + H)⁺ = 0.6 FM1 (KBr):C═O as solvent 744/6/8 (Br₂) 1618; 1680 228 N69 AS1 A0 C8 1 THF/DMF 69ESI: (M + H)⁺ = 0.45 FM1 (KBr): C═O as solvent 745/7/9 (Br₂) 1628 229N70 AS1 A0 C4 1 THF/DMF 39 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O as solvent727/29/31 (Br₂) 1730 230 N66 AS4 A0 C20 1 49 ESI: (M + H)⁺ = 0.55 FM1(KBr): C═O 758/60/62 (Br₂) 1614 231 N99 AS4 A0 C8 1 THF/DMF as 68 ESI:M + H)⁺ = 0.6 FM1 (KBr): C═O solvent 758/60/62 (Br₂) 1624 239 N71 AS1 A0C8 1 THF/DMF as 59 ESI: (M + H)⁺ = 0.45 FM1 (KBr): C═O solvent 757/59/61(Br₂) 1626; 1680 240 N71 AS4 A0 C11 1 35 ESI: (M + H)⁺ = 0.68 FM1 (KBr):C═O 771/3/5 (Br₂) 1615; 1684 241 N71 AS4 A0 C8 1 88 ESI: (M + H)⁺ = 0.68FM1 (KBr): C═O 756/58/60 (Br₂) 1620; 1682 242 N71 AS4 A0 C1 1 40 ESI:(M + H)⁺ = 0.64 FM1 (KBr): C═O 751/3/5 (Br₂) 1615; 1684 243 N71 AS4 A0C20 1 38 ESI: (M + H)⁺ = 0.65 FM1 (KBr): C═O 770/2/4 (Br₂) 1618; 1684244 N71 AS1 A0 C11 1 36 ESI: (M + H)⁺ = 0.35 FM1 (KBr): C═O 772/4/6(Br₂) 1622; 1684 N5 AS1 A3 C1 1 NEt₃ as base 24 ESI: (M + H)⁺ = 0.06 FM1(KBr): C═O 890/2/4 (Br₂) 1641.3 N10 AS1 A3 C1 1 NEt₃ as base 55 ESI:(M + H)⁺ = 0.38 FM1 (KBr): C═O 874/6/8 (Br₂) 1641.3 N12 AS1 A3 C1 1 NEt₃as base 35480 ESI: (M + H)⁺ = 0.43 FM1 (KBr): C═O 902/4/6 (Br₂) 1639.4N22 AS1 A3 C1 1 NEt₃ as base 35.5 0.5 FM1 N23 AS1 A3 C1 1 NEt₃ as base31 0.5 FM1 N24 AS1 A3 C1 1 NEt₃ as base 35607 0.5 FM1 N46 AS1 A3 C1 1NEt₃ as base 36.2 0.5 FM1 (KBr): C═O 1641.3 83 N15 AS1 A0 C1 1 36.7 ESI:(M + H)⁺ = 0.62 FM2 (KBr): C═O 726/28/30 (Br₂) 1641.3; 1695.3 84 N15 AS1A0 C4 1 36.3 ESI: (M + H)⁺ = 0.69 FM2 (KBr): C═O 725/7/9 (Br₂); 1624.0;(M + Na)⁺ = 1699.2 747/49/51 (Br₂) 88 N55 AS4 A0 C1 1 93.6 ESI: (M + H)⁺= 0.75 FM3 (KBr): C═O 793/5/7/9 1641.3; (Br₂; Cl₂) 1708.8 89 N56 AS4 A0C1 1 30 ESI: (M + H)⁺ = 0.81 FM1 (KBr): C═O 797/799/801 1641.3; (Br₂)1697.3; 1749.3 136 N15 AS9 A0 C1 1 14.6 ESI: (M + H)⁺ = 0.55 FM3 (KBr):C═O 570 1635.5; 1701.1 91 N64 AS4 A0 C1 1 11.7 ESI: (M + H)⁺ = 0.62 FM3(KBr): C═O 731/733/735 1625.9; 1685.7 N16 AS1 A3 C5 1 Purification 74ESI: (M + H)⁺ = 0.48 FM4 (KBr): C═O by column 974/976/978 1685.7;chromato- (Br₂) 1635.5 graphy: silica gel/FM4 155 N15 AS1 A0 C3 1 34ESI: (M + H)⁺ = 0.45 FM1 (KBr): C═O 165-9 743/5/7 (Br₂) 1626; 1695 156N15 AS1 A0 C19 1 40 ESI: (M + H)⁺ = 0.47 FM1 (KBr): C═O 155-9 743/5/7(Br₂) 1624; 1695 157 N15 AS4 A0 C19 1 54 ESI: (M + H)⁺ = 0.79 FM1 (KBr):C═O 151-4 742/4/6 (Br₂) 1616; 1697 158 N79 AS4 A0 C1 1 15 ESI: (M + H)⁺= 0.63 FM1 (KBr): C═O 132-5 727/29/31 (Br₂) 1616; 1695; 1732 159 N77 AS4A0 C8 1 34 ESI: (M + H)⁺ = 0.63 FM1 (KBr): C═O 732/4/6 (Br₂) 1632 160N73 AS1 A0 C4 1 12 ESI: (M − H)⁻ = 0.14 FM1 (KBr): C═O 649/651/653 1626(Br₂) 170 N15 AS4 A0 C37 1 62 ESI: (M − H)⁻ = 0.45 FM1 (KBr): C═O 165-70725/7/9 (Br₂) 1620; 1701 171 N79 AS1 A0 C1 1 60 ESI: (M + H)⁺ = 0.21 FM1(KBr): C═O 193-7 728/30/32 (Br₂) 1637.5 172 N79 AS1 A0 C8 1 27 ESI: (M +H)⁺ = 0.32 FM1 (KBr): C═O 163-9 733/5/7 (Br₂) 1622 185 N77 AS4 A0 C4 166 ESI: (M + H)⁺ = 0.49 FM1 (KBr): C═O 726/28/30 (Br₂) 1624 186 N77 AS4A0 C1 1 76 ESI: (M + H)⁺ = 0.63 FM1 (KBr): C═O 727/29/31 (Br₂) 1635.5187 N77 AS1 A0 C4 1 67 ESI: (M + H)⁺ = 0.33 FM1 (KBr): C═O 727/29/31(Br₂) 1627.8 188 N78 AS1 A3 C1 1 63 ESI: (M + H)⁺ = 0.45 FM1 (KBr): C═O955/7/9 (Br₂) 1637.5; 1774.4; 1701 189 N103 AS4 A0 C8 1 50 ESI: (M + H)⁺= 0.71 FM1 (KBr): C═O 713/5/7 (Br₂) 1616.3 192 N77 AS1 A0 C1 1 47 ESI:(M + H)⁺ = 0.2 FM1 (KBr): C═O 728/30/32 (Br₂) 1643.3 247 N15 AS10 A3 C41 60 ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O 937/39/41 (Br₂) 1639.4; 1701 249N15 AS4 A0 C22 1 52 ESI: (M + H)⁺ = 0.59 FM1 (KBr): C═O 744/6/8 (Br₂)1695.3 161 N15 AS4 A0 C21 1 32 ESI: (M + H)⁺ = 0.61 FM1 (KBr): C═O 163-7726/28/30 (Br₂) 1622: 1701 162 N78 AS1 A0 C4 1 15 ESI: (M + H)⁺ = 0.48FM1 (KBr): C═O 726/28/30 (Br₂) 1624; 1772.5 163 N73 AS1 A0 C1 1 43 ESI:(M + H)⁺ = 0.07 FM1 (KBr): C═O 752/4/6 (Br₂) 1637.5 164 N79 AS4 A0 C8 148 ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O 127-32 732/4/6 (Br₂) 1616.3 165N15 AS1 A0 C21 1 27 ESI: (M + H)⁺ = 0.26 FM1 (KBr): C═O 184-9 727/29/31(Br₂) 1697.3 166 N76 AS1 A0 C4 1 17 ESI: (M + H)⁺ = 0.23 FM1 (KBr): C═O665/7/9 (Br₂) 1616; 1734 167 N75 AS1 A0 C4 1 20 ESI: (M + H)⁺ = 0.18 FM1(KBr): C═O 665/7/9 (Br₂) 1624 168 N73 AS1 A3 C4 1 39 ESI: (M + H)⁺ =0.15 FM1 (KBr): C═O 879/81/83 (Br₂) 1631.7 169 N15 AS1 A0 C37 1 17 ESI:(M + H)⁺ = 0.31 FM1 (KBr): C═O 156-61 726/28/30 (Br₂) 1627.8; 1697.3 173N15 AS10 A0 C4 1 66 ESI: (M + H)⁺ = 0.68 FM1 (KBr): C═O 283-4 709/11/13(Br₂) 1627.8; 1656.8; 1695.3 174 N15 AS10 A0 C1 1 42 ESI: (M + H)⁺ =0.61 FM1 (KBr): C═O 266-9 710/2/4 (Br₂) 1706.9 175 N77 AS1 A0 C8 1 36ESI: (M + H)⁺ = 0.24 FM1 (KBr): C═O 733/5/7 (Br₂) 1641.3 176 N76 AS1 A3C4 1 47 ESI: (M + H)⁺ = 0.21 FM1 (KBr): C═O 893/5/7 (Br₂) 1635.5 177 N75AS1 A3 C4 1 53 ESI: (M + H)⁺ = 0.14 FM1 (KBr): C═O 893/5/7 (Br₂) 1637.5180 N74 AS1 A3 C4 1 44 ESI: (M + H)⁺ = 0.26 FM1 (KBr): C═O 907/9/11(Br₂) 1631.7; 1689.5 190 N15 AS1 A3 C18 1 44 ESI: (M + H)⁺ = 0.38 FM1(KBr): C═O 985/7/9 (Br₂) 1635.5; 1695.3 191 N15 AS10 A3 C1 1 64 ESI:(M + H)⁺ = 0.56 FM1 (KBr): C═O 938/40/42 (Br₂) 1645.2; 1701 N15 AS10 A3C4 1 91 ESI: (M + H)⁺ = (KBr): C═O 937/39/41 (Br₂) 1643.3; 1701 N15 AS10A3 C1 1 64 ESI: (M + H)⁺ = (KBr): C═O 938/40/42 (Br₂) 1645; 1701 254 N77AS1 A3 C1 1 37 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O 956/8/60 (Br₂) 1641N15 AS4 A3 C18 1 90 ESI: (M + H)⁺ = (KBr): C═O 984/6/8 (Br₂) 1641.3;1699 257 N15 AS4 A5 C1 1 17 ESI: (M + H)⁺ = 0.53 FM1 (KBr): C═O 782/4/6(Br₂) 1643; 1697 258 N100 AS4 A0 C1 1 69 ESI: (M + H)⁺ = 0.54 FM1 (KBr):C═O 755/7/9 (Br₂) 1627.8; 1705 259 N100 AS4 A0 C8 1 70 ESI: (M + H)⁺ =0.54 FM1 (KBr): C═O 760/2/4 (Br₂) 1695 260 N15 AS4 A0 C23 1 39 ESI: (M +H)⁺ = 0.36 FM1 (KBr): C═O 796/798/800 1635.5; 1699 (Br₂) 261 N15 AS4 A10C1 1 26 ESI: (M + H)⁺ = 0.38 FM1 (KBr): C═O 796/798/800 1631.4; 1701(Br₂) 265 N15 AS4 A5 C8 1 20 ESI: (M + H)⁺ = 0.41 FM1 (KBr): C═O787/9/91 (Br₂) 1635.5; 1697 266 N15 AS4 A6 C1 1 24 ESI: (M + H)⁺ = 0.43FM1 (KBr): C═O 796/798/800 1647; 1689.5 (Br₂) 262 N80 AS4 A0 C1 1 25ESI: (M + H)⁺ = 0.54 FM1 (KBr): C═O 803/5/7 (Br₂) 1637.5 263 N15 AS15 A0C8 1 64 ESI: (M + H)⁺ = 0.43 FM1 (KBr): C═O 565 1627.8; 1707 264 N15 AS4A0 C24 1 62 ESI: (M + H)⁺ = 0.4 FM1 (KBr): C═O 733/5/7 (Br₂) 1622; 1701267 N81 AS4 A3 C8 1 46 ESI: (M + H)⁺ = 0.55 FM1 (KBr): C═O 974/6/8 (Br₂)1641; 1707 268 N15 AS4 A6 C8 1 27 ESI: (M + H)⁺ = 0.5 FM1 (KBr): C═O801/3/5 (Br₂) 1633.6; 1697 269 N82 AS4 A0 C8 1 86 ESI: (M + H)⁺ = 0.66FM1 (KBr): C═O 742/4/6 (Br₂) 1620; 1649 270 N82 AS4 A0 C1 1 56 ESI: (M +H)⁺ = 0.59 FM1 (KBr): C═O 737/39/41 (Br₂) 1641 272 N15 AS11 A0 C8 1 76ESI: (M + H)⁺ = 0.6 FM1 (KBr): C═O 698 1627.8; 1714.6 273 N15 AS4 A10 C81 68 ESI: (M + H)⁺ = 0.52 FM1 (KBr): C═O 801/3/5 (Br₂) 1637.5; 1701 274N102 AS4 A0 C1 1 76 ESI: (M + H)⁺ = 0.56 FM1 (KBr): C═O 738/40/42 (Br₂)1664.5 275 N102 AS4 A0 C8 1 55 ESI: (M + H)⁺ = 0.59 FM1 (KBr): C═O743/5/7 (Br₂) 1618; 1664.5 276 N83 AS4 A0 C1 1 30 ESI: (M + H)⁺ = 0.48FM1 (KBr): C═O 745/7/9 (Br₂) 1633.6 277 N84 AS4 A0 C8 1 63 ESI: (M + H)⁺= 0.54 FM1 (KBr): C═O 744/6/8 (Br₂) 1616; 1691.5 278 N84 AS4 A3 C4 1 88ESI: (M + H)⁺ = 0.53 FM1 (KBr): C═O 966/8/70 (Br₂) 1633.6; 1691.5 279N15 AS4 A0 C26 1 75 ESI: (M + H)⁺ = 0.44 FM1 (KBr): C═O 732/4/6 (Br₂)1618; 1709 281 N15 AS12 A0 C8 1 21 ESI: (M + H)⁺ = 0.42 FM1 (KBr): C═O598 1697 282 N66 AS1 A0 C18 1 19 ESI: (M + H)⁺ = 0.51 FM1 (KBr): C═O770/2/4 (Br₂) 1624; 1660.6; 1734 284 N66 AS1 A0 C18 1 29 ESI: (M + H)⁺ =0.3 FM1 (KBr): C═O 771/3/5 (Br₂) 1630; 1655 314 N93 AS4 A0 C8 1 81 ESI:(M + H)⁺ = 0.5 FM1 (KBr): C═O 794/6/8 (Br₂) 1618; 1701 315 N93 AS4 A0 C11 77 ESI: (M + H)⁺ = 0.49 FM1 (KBr): C═O 789/91/93 (Br₂) 1627.6; 1705316 N65 AS1 A0 C18 1 15 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O 783/5/7 (Br₂)1624; 1681.8 317 N66 AS4 A0 C3 1 51 ESI: (M + H)⁺ = 0.62 FM1 (KBr): C═O778/80/82 (Br₂) 1627.6; 1662.5 318 N66 AS1 A0 C3 1 40 ESI: (M + H)⁺ =0.41 FM1 (KBr): C═O 557/579/561 1659 (Br₂) 319 N66 AS4 A0 C19 1 55 ESI:(M + H)⁺ = 0.68 FM1 (KBr): C═O 778/780/782 1664.5 (Br₂) 320 N65 AS4 A0C19 1 61 ESI: (M + H)⁺ = 0.62 FM1 (KBr): C═O 768/70/72 (Br₂) 1618; 1682321 N93 AS1 A0 C4 1 29 ESI: (M + H)⁺ = 0.35 FM1 (KBr): C═O 789/91/93(Br₂) 1622; 1705 N15 AS1 A3 C5 1 47 0.32 FM1 N19 AS1 A3 C1 1 80 ESI:(M + H)⁺ = (KBr): C═O 933/5/7 (Br₂) 1641.3

EXAMPLE 5

Preparation of compounds of general formula:

1-[N²-[N-(4-phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine(No. 17)

To a solution of 800 mg (0.86 mmol) of1-[N²-[N-(4-phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazinein methanol were added 2 ml of methanol saturated with hydrogen chlorideand the mixture was stirred overnight at ambient temperature. Thereaction mixture was mixed with ethyl acetate until the hydrochloridewas totally precipitated and the precipitate formed was filtered off.After washing the precipitate with water it was purified by columnchromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM,eluant: ethyl acetate/methanol/conc. aqueous ammonia=5/5/0.5 (v/v/v)).0.38 g (55% of theory) of an amorphous solid were obtained.

IR (KBr): 1639 cm⁻¹ (C═O)

R_(f): 0.55 (FM2)

ESI-MS: (M+H)⁺=799/801/803 (Br₂) (M+2H)⁺⁺=400/401/402 (Br₂)

The following were prepared analogously (in each case n=1):

No. RCO R² A n NR³R⁴ % Yield MS R_(f) Elaunt IR [cm⁻¹] 11 N8 AS1 A1 1 C170 ESI: (M + H)⁺ = 0.43 FM2 (KBr): C═O 758/60/62 (Br₂) 1656.8 12 N9 AS1A1 1 C1 60 ESI: (M + H)⁺ = 0.46 FM2 (KBr): C═O 788/90/92 (Br₂) 1643.3  8N5 AS1 A1 1 C1 53.7 ESI: (M + H)⁺ = 0.2 methanol/ (KBr): C═O 790/2/4(Br₂) glacial acetic 1641.3 acid/water = 9/1/1 (v/v/v) 15 N11 AS1 A1 1C1 56 ESI: (M + H)⁺ = 0.4 FM2 773/5/7 (Br₂)  6 N2 AS1 A1 1 C11 66.4 ESI:(M + H)⁺ = 0.39 FM2 (KBr): C═O 808/10/12 (Br₂) 1656.8  7 N2 AS1 A1 1 C246.2 ESI: (M + H)⁺ = 0.13 FM2 (KBr): C═O 794/6/8 (Br₂) 1637.5 13 N2 AS2A1 1 C1 84.7 ESI: (M + H)⁺ = 0.46 FM2 (KBr): C═O 666 1641.3

EXAMPLE 6

Preparation of compounds of general formula:

1-[4-amino-3,5-dibromo-N²-[N-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-bis-trifluoroacetate)(No. 61)

To a mixture of 0.42 g (0.45 mmol) of1-[4-amino-3,5-dibromo-N²-[N-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanyl]-N6-[(1.1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazinein 30 ml of methylene chloride were added 3 ml of trifluoroacetic acid.The reaction mixture was stirred for 3 hours at ambient temperature andthen evaporated down in vacuo. The remaining residue was triturated withether and the resulting beige amorphous solid (0.43 g; 37% of theory)was suction filtered.

IR (KBr): 1643, 1678 cm⁻¹ (C═O)

R_(f): 0.6 (FM1)

ESI-MS: (M+H)⁺=832/834/836/838 (Br₂, Cl)

The following were prepared analogously:

% No. RCO Z R² A NR³R⁴ n Remarks Yield MS R_(f) Eluant IR [cm⁻¹] 21 N6N—H AS1 A1 C4 1 65 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O 828/30/32 (Br₂)1635.5 22 N16 N—H AS1 A1 C1 1 98 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O874/6/8 (Br₂) 1643.3; 1676 141 N61 N—H AS1 A1 C1 1 46 ESI: (M + H)⁺ =0.1 FM1 (KBr): C═O 855/7/9 (Br₂) 1634; 1705 142 N60 N—H AS1 A1 C1 1 50ESI: (M + H)⁺ = 0.1 FM1 (KBr): C═O 882/4/6 (Br₂) 1643; 1711 154 N66 N—HAS1 A1 C1 1 60 ESI: (M + H)⁺ = 0.1 FM1 (KBr): C═O 868/70/72 (Br₂) 1645;1653 197 N15 N—H AS1 A1 C8 1 21 ESI: (M + H)⁺ = 0.18 FM7 (KBr): C═O859/61/63 (Br₂) 1678; 1201.6; CF3 1180.4; 1134.1 198 N51 N—H AS1 A1 C8 127 ESl: (M + H)⁺ = 0.22 FM7 (KBr): C═O 829/31/33 (Br₂) 1676; CN 2221.9;CF3 1203.5; 1180.4; 1132 218 N15 N—H AS6 A1 C1 1 25.7 ESI: (M + H)⁺ =0.45 FM1 (KBr): C═O 776/8 (Br) 1695.3; 1635.5 287 N15 N—H AS1 A8 C1 136.5 ESI: (M + H)⁺ = 0.5 FM2 (KBr): C═O 840/2/4 (Br₂) 1695.3; 1637.5 19N15 N—H AS1 A1 C1 1 44 ESI; (M + H)⁺ = 0.43 FM2 (KBr): C═O 854/6/8 (Br₂)1695.3; 1637.5 14 N10 N—H AS1 A1 C1 1 25.5 ESI: (M + H)⁺ = 0.33 FM2(KBr): C═O 774/6/8 (Br₂) 1683.8 16 N12 N—H AS1 A1 C1 1 64.4 ESI: (M +H)⁺ = 0.55 FM2 (KBr): C═O 802/4/6 (Br₂) 1639.4 29 N22 N—H AS1 A1 C1 191.2 ESI: (M + H)⁺ = 0.5 FM2 (KBr): —NH— 867/69/71 (Br₂) 3427.3; C═O1643.3; 1678.0 30 N23 N—H AS1 A1 C1 1 83.3 ESI: (M + H)⁺ = 0.5 FM2(KBr): C═O 833/5/7/9 (Br₂, Cl) 1643.3; 1676.0 31 N24 N—H AS1 A1 C1 1 100ESI: (M + H)⁺ = 0.51 FM2 (KBr): C═O 843/5/7 (Br₂) 1645.2; 1676.0 63 N46N—H AS1 A1 C1 1 100 ESI: (M + H)⁺ = 0.58 FM2 (KBr): C═O 764/6/8 (Br₂)1643.3; 1676.0 68 N15 N—H AS1 A1 C6 1 80 ESI: (M + H)⁺ = 0.18 FM1 (KBr):C═O 833/5/7 (Br₂) 1683.8 69 N15 N—H AS1 A1 C5 1 74 ESI: (M + H)⁺ = 0.18FM1 (KBr): C═O 854/6/8 (Br₂) 1683.8; 1639.4 70 N45 N—H AS1 A1 C6 1 89ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 897/9/901 (Br₂) 1695.3; 1676.0 71 N16N—H AS1 A1 C5 1 82 ESI: (M + H)⁺ = 0.22 FM1 (KBr): C═O 874/6/8 (Br₂)1678.0; 1639.4 72 N15 N—H AS5 A1 C1 1 97 ESI: (M + H)⁺ = 0.16/0.2 FM1(KBr): C═O 838/40/42 (Br₂) 1685.7; 1643.3 77 N45 N—H AS5 A1 C1 1 66 ESI:(M + H)⁺ = 0.33/0.4 FM1 (KBr): C═O 852/4/6 (Br₂) 1683.8; 1645.2 NH₃3427.3 24 N18 N—H AS1 A1 C1 1 94 ESI: (M + H)⁺ = 0.11 FM1 (KBr): C═O775/7/9 (Br₂) 1676.0; 1643.3 25 N19 N—H AS1 A1 C1 1 92 ESI: (M + H)⁺ =0.13 FM1 (KBr): C═O 833/5/7 (Br₂) 1676.0; 1643.3 26 N20 N—H AS1 A1 C1 198 EI: M⁺ = 762/4/6 0.11 FM1 (KBr): C═O (Br₂) 1676.0; 1643.3 27 N21 N—HAS1 A1 C1 1 98 ESI: (M + H)⁺ = 0.04 FM1 (KBr): C═O 814/6/8 (Br₂) 1676.0;1645.2 41 N34 N—H AS1 A1 C1 1 97 ESI: (M + H)⁺ = 0.08 FM1 (KBr): C═O835/38/40/42 1676.0; (Br₃) 1643.3 42 N35 N—H AS1 A1 C1 1 83 ESI: (M +H)⁺ = 0.09 FM1 (KBr): C═O 803/5/7 (Br₂) 1676.0; 1643.3 43 N36 N—H AS1 A1C1 1 87 ESI: (M + H)⁺ = 0.04 FM1 (KBr): C═O 815/7/9 (Br₂) 1676.0; 1645.253 N42 N—H AS1 A1 C1 1 89 ESI: (M + H)⁺ = 0.11 FM1 (KBr): C═O 805/7/9(Br₂) 1676.0; 1634.3 54 N43 N—H AS1 A1 C1 1 84 ESI: (M + H)⁺ = 0.11 FM1(KBr): C═O 835/7/9/41 (Br₃) 1678.0; 1643.3 55 N44 N—H AS1 A1 C1 1 95ESI: (M + H)⁺ = 0.07 FM1 (KBr): C═O 796/8/800 (Br₂) 1676.0; 1643.3 67N48 N—H AS1 A1 C1 1 90 ESI: (M + H)⁺ = 0.06 FM1 (KBr): C═O 797/99/801(Br₂) 1682.9; 1643.3 184 N77 N—H AS1 A1 C4 1 88 ESI: (M + H)⁺ = 0.11 FM1(KBr): C═O 855/7/9 (Br₂) 1637.5; 1676 248 N78 N—H AS1 A1 C1 1 97 ESI:(M + H)⁺ = 0.14 FM1 (KBr): C═O 855/7/9 (Br₂) 1643.3; 1676; 1772.5 181N75 N—H AS1 A1 C4 1 95 ESI: (M + H)⁺ = 0.04 FM1 (KBr): C═O 793/5/7 (Br₂)1637.5; 1676 182 N76 N—H AS1 A1 C4 1 93 ESI: (M + H)⁺ = 0.04 FM1 (KBr):C═O 793/5/7 (Br₂) 1637.5; 1678 183 N74 N—H AS1 A1 C4 1 91 ESI: (M + H)⁺= 0.08 FM1 (KBr): C═O 807/9/11 (Br₂) 1635.5; 1678 250 N15 N—H AS1 A1 C181 98 ESI: (M + H)⁺ = 0.14 FM1 (KBr): C═O 885/7/9 (Br₂) 1633.6; 1680 251N15 N—H AS10 A1 C4 1 84 ESI: (M + H)⁺ = 0.27 FM1 (KBr): C═O 837/39/41(Br₂) 1635.5; 1693.4 252 N15 N—H AS10 A1 C4 1 87 ESI: (M + H)⁺ = 0.31FM1 (KBr): C═O 837/39/41 (Br₂) 1637.5; 1685.7 253 N15 N—H AS10 A1 C1 182 ESI: (M + H)⁺ = 0.18 FM1 (KBr): C═O 838/40/42 (Br₂) 1690 255 N77 N—HAS1 A1 C1 1 94 ESI: (M + H)⁺ = 0.08 FM1 (KBr): C═O 856/8/60 (Br₂) 1645;1676 256 N15 N—H AS4 A1 C18 1 74 ESI: (M + H)⁺ = 0.28 FM1 (KBr): C═O884/6/8 (Br₂) 1633.6; 1683.8 271 N81 N—H AS4 A1 C8 1 76 ESI: (M + H)⁺ =0.2 FM1 (KBr): C═O 874/6/8 (Br₂) 1674 280 N84 N—H AS4 A1 C4 1 66 ESI:(M + H)⁺ = 0.26 FM1 (KBr): C═O 866/8/70 (Br₂) 1635.5; 1685.7 N15 N—H AS1A1 C1 0 98 ESI: (M + H)⁺ = 0.2 ButOH/ (KBr): C═O 840/2/4 (Br₂) ACOH/H2O= 1643; 1680 4/1/1 (v/v/v) 179 N73 N—H AS1 A1 C4 1 86 ESI: (M + H)⁺ =0.03 FM1 (KBr): C═O 779/81/83 (Br₂) 1642.8; 1676 N66 N—H AS4 A0 1 75ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O 744/6/8 (Br₂) 1620/1666 516 N66 N—HAS1 A1 C1 1 Isomer to 82 0.1 FM1 No. (154) 517 N66 N—H AS1 A1 C1 1Isomer to 80 0.1 FM1 No. (154) 518 N66 N—H AS1 A1 C1 1 Isomer to 89 0.1FM1 No. (154) 521 N66 N—H AS4 A0 C17 1 THF/DMF 75 ESI: (M + H)⁺ = 0.15FM1 (KBr): C═O 744/6/8 (Br₂) 1666/1620 522 N66 N—H AS1 A0 C17 1 THF/DMF100 ESI: (M + H)⁺ = 0.15 FM1 (KBr): C═O 745/7/9 (Br₂) 1624/1655 643 N66CH₂ AS21 A0 C17 1 53 ESI: (M + H)⁺ = 0.35 FM1 (KBr): C═O 640 1635/1668N66 CH₂ AS2 A0 C17 1 100 EI: M⁺ = 621 0.35 FM1 (KBr): C═O 1670

EXAMPLE 7

Preparation of compounds of general formula:

1-[N²-[N-[[[(2-methoxyphenyl)methyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

A mixture of 910 mg (1.0 mmol) of1-[N²-[N-[[[2-(2-methoxy-phenyl)methyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-N⁶-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,50 ml of glacial acetic acid, 25 ml of a 33% solution of hydrogenbromide in glacial acetic acid and 2 ml of anisole was stirred overnightat ambient temperature. The reaction mixture was stirred intodiethylether and the sticky precipitate formed was suction filtered. Thecrude product was purified by column chromatography (MN-silica gel 60,Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc.aqueous ammonia=8/2/0.2 (v/v/v)). 0.37 g (48% of theory) of an amorphoussolid were obtained.

IR (KBr): 1630 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=774/776/778 (Br₂) (M+2H)⁺⁺=387.7/388.7/389.7 (Br₂)

The following were prepared analogously (in each case n=1):

% No. RCO R² A NR³R⁴ Yield MS R_(f) Eluant IR [cm⁻¹ ] 1 N1 AS1 A1 C146.9 ESI: (M + H)⁺ = 0.36 FM1 (KBr): C═O 788/90/92 (Br₂) 1627.8 2 N2 AS1A1 C1 100 ESI: (M + H)⁺ = 0.48 FM2 (KBr): C═O 788/90/92 (Br₂) 1641.3;NH, NH⁺ 3419.6 4 N4 AS1 A1 C1 2.8 ESI: (M + H)⁺ = 0.52 FM2 818/20/22(Br₂)

EXAMPLE 8

Preparation of compounds of general formula:

1-[N²-[N-[4-(4-fluorophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-N⁶-[(1.1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine

To a solution of 0.18 g (0.001 mol) 4-(4-fluorophenyl)-butanoic acid ina mixture of 4 ml of dimethylformamide and 10 ml of tetrahydrofuran wasadded with stirring a mixture of 0.71 g (0.001 mol)1-[N2-(3,5-dibromo-D-tyrosyl)-N⁶-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,0.32 g (0.001 mol) TBTU and 0.13 g (0.001 mol) DIEA and the mixture wasstirred in a nitrogen atmosphere for 2 days. The reaction mixture wasthen evaporated down in vacuo and the remaining residue was taken up indichloromethane. The organic phase was with 20% aqueous citric acidsolution and then extracted with 10% aqueous sodium hydrogen carbonatesolution, dried over sodium sulphate, filtered and evaporated down invacuo. After stirring the residue with ether 0.68 g (77% of theory) ofthe desired product remain as an amorphous residue.

IR (KBr): 1641, 1676 cm⁻¹ (C═O)

R_(f): 0.65 (FM2)

ESI-MS: (M+H)⁺=875/877/879 (Br₂) (M+H+Na)⁺⁺=449/450/451 (Br₂)

The following were prepared analogously (in each case n=1):

% No. RCO R² A NR³R⁴ Remarks Yield MS R_(f) Eluant IR [cm⁻¹] 123 N62 AS1A0 C1 DMF/THF as 20 ESI: (M + H)⁺ = 0.3 FM1 (KBr): C═O solvent 725/7/9(Br₂) 1641.3; 1691.5 124 N63 AS1 A0 C1 DMF/THF as 53 ESI: (M + H)⁺ = 0.2FM1 (KBr): C═O solvent 725/7/9 (Br₂) 1641.3; 1691.5 322 N63 AS1 A0 C8DMF/THF as 19 EI: M⁺ = 0.3 FM1 (KBr): C═O solvent 729/31/33 (Br₂)1629.8; 1695.3 N11 AS1 A3 C1 46 ESI: (M + H)⁺ = (KBr): C═O 873/5/7 (Br₂)1625.9; 1645.2 N18 AS1 A3 C1 THF/DMF as 77 ESI: (M + H)⁺ = 0.78 FM7(KBr): C═O solvent 875/7/9 (Br₂) 1641.3 N20 AS1 A3 C1 THF/DMF as 88 ESI:(M + H)⁺ = 0.67 FM7 (KBr): C═O solvent 863/5/7 (Br₂) 1643.3 N21 AS1 A3C1 THF/DMF as 78 ESI: (M + H)⁺ = 0.47 FM7 (KBr): C═O solvent 917/6/8(Br₂) 1643.3 N46 AS1 A3 C1 THF/DMF as 80 ESI: (M + H)⁺ = 0.65 FM7 (KBr):C═O solvent 905/7/9 (Br₂) 1643.3 N43 AS1 A3 C1 THF/DMF as 75 0.75 FM7(KBr): C═O solvent 1645.2 N44 AS1 A3 C1 THF/DMF as 79 ESI: (M + H)⁺ =0.65 FM7 (KBr): C═O solvent 896/98/900 1629.8 (Br₂)

EXAMPLE 9

Preparation of compounds of general formula:

1-[N²-[N-[[[(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dichloro-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-bis-(trifluoroacetate(No. 20)

To a suspension of 0.33 g (2 mmol) of CDT and 1 ml of triethylamine inabout 30 ml of tetrahydrofuran, cooled to −10° C., was added dropwise,with stirring, a solution of 1.0 g (1.6 mmol) of1-[N²(-3.5-dichloro-D-tyrosyl]-N⁶-[(1.1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazinein 50 ml of tetrahydrofuran within 60 minutes. The reaction mixture wasstirred for 1 hour at 0° C., then stirred for 2 hours at ambienttemperature, mixed with a tetrahydrofuran solution of 0.24 g (1.6 mmol)of (3-methoxyphenyl)-ethanamine, refluxed for 3 hours and stirredovernight at ambient temperature. After elimination of the solvent invacuo the residue was purified by column chromatography (MN-silica gel60, Macherey-Nagel, 70-230 mesh ASTM, eluant: FM1). The resultingintermediate compound was stirred in a mixture of 5 ml oftrifluoroacetic acid and 80 ml of dichloromethane overnight, the solventwas eliminated in vacuo and the residue triturated with ether. 709 mg(43% of theory) of the desired compound as an amorphous solid.

IR (KBr): 1643, 1676 cm⁻¹ (C═O)

R_(f): 0.41 (FM2)

ESI-MS: (M+H)⁺=700/702/704 (Br₂) (M+2H)⁺⁺=350.7/351.7/352.7 (Br₂)

The following were prepared analogously (in each case n=1):

% No. RCO R² A NR³R⁴ Remarks Yield MS R_(f) Eluant IR [cm⁻¹] 23 N17 AS1A1 C1 NEt₃ as base 55 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 798/800/802(Br₂) 1643.3; 1676 47 N39 AS1 A1 C1 NEt₃ as base 69.4 ESI: (M + H)⁺ =0.1 FM1 (KBr): C═O 676/78/80 (Br₂) 1645.2; 1676 50 N64 AS1 A1 C1 NEt₃ asbase 76 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 828/830/832 (Br₂) 1643.3;1678 51 N40 AS1 A1 C1 NEt₃ as base; 79.7 ESI: (M + H)⁺ = 0.2 FM1 (KBr):C═O dehydration 826/828/30 (Br₂) 1643.3; 1678 52 N41 AS1 A1 C1 NEt₃ asbase; 21.8 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O dehydration 826/828/30(Br₂) 1645.2; 1679.9 56 N16 AS1 A1 C4 NEt₃ as base 5 ESI: (M + H)⁺ = 0.3FM1 (KBr): C═O 873/75/77 (Br₂) 1637.5; 1676 57 N45 AS1 A1 C4 NEt₃ asbase 32 ESI: (M + H)⁺ = 0.2 FM1 (KBr): C═O 867/9/71 (Br₂) 1635.5; 167866 N47 AS1 A1 C4 NEt₃ as base 28.4 ESI: (M + H)⁺ = 0.1 FM1 (KBr): C═O764/6/8 (Br₂) 1635.5; 1676 46 N38 AS1 A1 C1 NEt₃ as base 86 ESI: (M +H)⁺ = 0.35 FM1 (KBr): C═O 826/28/30 (Br₂) 1645.2; 1684 232 N66 AS4 A1 C869 ESI: (M + H)⁺ = 0.33 FM1 (KBr): C═O 872/4/6 (Br₂) 1645 233 N66 AS4 A1C1 THF/DMF as 16 ESI: (M + H)⁺ = 0.32 FM1 (KBr): C═O solvent 867/69/71(Br₂) 1653 234 N66 AS4 A1 C4 68 ESI: (M + H)⁺ = 0.42 FM1 (KBr): C═O867/69/71 (Br₂) 1645 235 N66 AS1 A1 C8 26 ESI: (M + H)⁺ = 0.27 FM1(KBr):C═O 873/5/7 (Br₂) 1645 236 N71 AS1 A1 C1 30 ESI: (M + H)⁺ = 0.22FM1 (KBr): C═O 880/2/4 (Br₂) 1636; 1678 237 N71 AS4 A1 C8 28 ESI: (M +H)⁺ = 0.25 FM1 884/6/8 (Br₂) 238 N71 AS4 A1 C1 20 ESI: (M + H)⁺ = 0.3FM1 (KBr): C═O 879/81/83 (Br₂) 1641; 1682 18 N14 AS1 A1 C1 Cleaving ofBoc 26.3 ESI: (M + H)⁺ = 0.55 FM2 (KBr): C═O protecting group with813/5/7 (Br₂) 1641.3; methanolic HCl 1716.5 solution 17 N13 AS1 A1 C1Cleaving of Boc 55.2 ESI: (M + H)⁺ = 0.55 FM2 (KBr): C═O protectinggroup with 799/801/803 (Br₂) 1639.4 methanolic HCl solution 9 N6 AS1 A1C1 Cleaving of Boc 41.3 ESI: (M + H)⁺ = 0.44 FM2 (KBr): C═O protectinggroup with 829/31/33 (Br₂) 1639.4 methanolic HCl solution 10 N7 AS1 A1C1 Cleaving of Boc 57.6 ESI: (M + H)⁺ = 0.32 FM2 (KBr): C═O protectinggroup with 829/31/33 (Br₂) 1639.4 methanolic HCl solution 20 N2 AS3 A1C1 43 ESI: (M + H)⁺ = 0.41 FM2 (KBr): C═O 700/2/4 (Br₂) 1643.3; 1676.0283 N102 AS4 A3 C4 NEt₃ as base 65 ESI: (M + H)⁺ = 0.24 FM1 (KBr): C═O864/6/8 (Br₂) 1637.5; 1676

EXAMPLE 10

Preparation of compounds of general formula:

1-[N²-[N-[4-(2,3-dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-tris-(trifluoroacetate)(No. 74)

To a solution of 0.35 g (2.1 mmol) of CDT in 50 ml of tetrahydrofuranwere added with cooling (0° C.) and stirring 1.0 g (1.4 mmol) of1-[N²-(3,5-dibromo-D-tyrosyl)-N⁶-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazineand the mixture was stirred for 30 minutes at 0° C. and for a further 30minutes at ambient temperature. After the addition of 0.47 g (1.75 mmol)of 1-(2,3-dichlorophenyl)piperazine-hydrochloride and 0.25 ml oftriethylamine the reaction mixture was refluxed for 5 hours and aftercooling mixed with 70 ml of saturated aqueous sodium hydrogen carbonatesolution. The organic phase was separated off, the aqueous phase wasextracted twice with 50 ml of tetrahydrofuran. The combined organicphases were washed with saturated aqueous saline solution, dried overmagnesium sulphate, filtered and evaporated down in vacuo. The residuewas triturated with ether, suction filtered and then stirred for 2 hourswith a mixture of 50 ml of dichloromethane and 5 ml of trifluoroaceticacid. After evaporation of the reaction mixture in vacuo and triturationof the residue with ether, 0.8 g (47% of theory) of an amorphous solidare left.

IR (KBr): 1643.3, 1676 cm⁻¹ (C═O)

R_(f): 0.78 (FM7)

ESI-MS: (M+H)⁺=867/869/871/873/875 (Br₂, Cl₂) (M+2H)⁺⁺=434/435/436/437(Br₂, Cl₂)

The following were prepared in the same way (in each case n=1):

% No. RCO R² A NR³R⁴ Yield MS R_(f) Eluant IR [cm⁻¹] 36 N29 AS1 A1 C117.3 ESI : (M + H)⁺ = 0.35 MeOH/NH_(4l OH =) (KBr): C═O 889/91/93 (Br₂)9/1 (v/v) 1643.3; 1674.1 208 N15 AS1 A1 C1 53.5 ESI: (M + H)⁺ = 0.43 FM2(KBr): C═O 854/6/8 (Br₂) 1691.5; 1635.5 209 N15 AS1 A1 C1 47.7 ESI: (M +H)⁺ = 0.55 FM2 (KBr): C═O 854/6/8 (Br₂) 1695.3; 1637.5 210 N15 AS1 A1 C128 ESI: (M + H)⁺ = 0.48 FM2 (KBr): C═O 854/6/8 (Br₂) 1689.5; 1639.4 75N50 AS1 A1 C1 16.5 ESI: (M + H)⁺ = 0.63 FM2 (KBr): C═O 867/69/71/73/751643.3; (Br₂, Cl₂) 1676.0; 74 N49 AS1 A1 C1 47 ESI: (M + H)⁺ = 0.65 FM2(KBr): C═O 867/69/71/73/75 1643.3; (Br₂, Cl₂) 1676.0 76 N51 AS1 A1 C113.4 ESI: (M + H)⁺ = 0.58 FM2 (KBr): C═O 824/6/8 (Br₂) 1643.3; 1676.0;CN 2219.9 79 N52 AS1 A1 C1 11.4 ESI: (M + H)⁺ = 0.59 FM2 (KBr): C═O901/3/5/7 (Br₂, 1645.2; Cl) 1676.3 45 N37 AS1 A1 C1 43 ESI: (M + H)⁺ =0.6 FM2 (KBr): C═O 784/6/8 (Br₂) 1643.3; 1678.0 39 N32 AS1 A1 C1 48.3ESI: (M + H)⁺ = 0.57 FM2 (KBr): C═O 795/7/9 (Br₂) 1643.3; 1678.0 38 N31AS1 A1 C1 54.1 ESI: (M + H)⁺ = 0.6 FM2 (KBr): C═O 844/6/8 (Br₂) 1643.3;1678.0; NO2 1543.0 37 N30 AS1 A1 C1 61.6 ESI: (M + H)⁺ = 0.6 FM2 (KBr):C═O 813/5/7 (Br₂) 1643.3; 1676.0 35 N28 AS1 A1 C1 74.8 ESI: (M + H)⁺ =0.55 FM2 (KBr): C═O 800/2/4 (Br₂) 1639.4; 34 N27 AS1 A1 C1 36.8 ESI:(M + H)⁺ = 0.43 FM2 (KBr): C═O 800/2/4 (Br₂) 1641.3; 1714.6; NH⁺ 3409.932 N25 AS1 A1 C1 50.0 ESI: (M + H)⁺ = 0.44 FM2 (KBr): C═O 737/39/41(Br₂) 1645.2; 1678.3 33 N26 AS1 A1 C1 42 ESI: (M + H)⁺ = 0.33 FM2 (KBr):C═O 767/69/71 (Br₂) 1676.0 40 N33 AS1 A1 C1 14.5 ESI: (M + H)⁺ = 0.58FM2 (KBr): C═O 802/4/6 (Br₂) 1643.3; 1676.0 28 N6 AS3 A1 C1 67.2 ESI:(M + H)⁺ = 0.43 FM2 (KBr): C═O 741/3/5 (Cl₂) 1641.3; 1716.5 64 N23 AS1A1 C4 39 ESI: (M + H)⁺ = 0.68 FM2 (KBr): C═O 832/4/6/8 1627.8; (Br₂, Cl)1678.0 65 N15 AS1 A1 C4 41 ESI: (M + H)⁺ = 0.61 FM2 (KBr): C═O 853/5/7(Br₂) 1631.7; 1695.3 365 N111 AS1 A1 C1 36.9 ESI: (M + H)⁺ = 0.09 FM1(KBr): C═O 839/41/43 (Br₂) 1626/1676

EXAMPLE 11

1-[N2-[N-[[[2-(2,5-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5dibromo-D,L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine (No. 3)

A mixture of 0.8 g (0.84 mmol) of1-[N²-[N-[[[2-(2,5-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N⁶-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,50 ml of glacial acetic acid, 25 ml of a 33% solution of hydrogenbromide in glacial acetic acid and 2 ml of anisole was stirred for 12hours at ambient temperature. The reaction mixture was stirred intodiethylether and the resulting precipitate was suction filtered. Thesolid residue was purified by column chromatography (MN-silica gel 60,Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc.aqueous ammonia=8/2/0.2 (v/v/v)). 0.3 g (44% of theory) of the desiredproduct was obtained as an amorphous solid.

IR (KBr): 1643.3 cm⁻¹ (C═O)

R_(f): 0.17 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1)

ESI-MS: (M+H)⁺=818/820/822 (Br₂) (M+2H)⁺⁺=409.5/410.5/411.5 (Br₂)

EXAMPLE 12

1-[N²-[3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazine-bis-(trifluoroacetate)(No. 4)

A stirred mixture of 20 ml of trifluoroacetic acid, 1.3 ml of anisoleand 0.9 ml of ethanedithiol was mixed with 2.1 g (1.9 mmol) of solid1-[N²-[3,5-dibromo-N-[[[2-(3-methoxyphenyl)-ethyl]amino]carbonyl]-N^(G)-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazinewhilst cooling with ice and stirred for a further 45 minutes whilstcooling with ice, then for 3 hours at ambient temperature. The resultingprecipitate was suction filtered and discarded, the filtrate wasevaporated down in vacuo, the residue remaining was mixed with tolueneand again evaporated down in vacuo. The resulting solid residue wastriturated with a mixture of diethylether and acetone and the whitesolid formed was suction filtered and dried. 1.7 g (65% of theory) ofthe desired title compound were obtained.

IR (KBr): 1674, 1645 cm⁻¹ (C═O)

R_(f): 0.15 (FM: BuOH/AcOH/H₂O 4/1/1 (v/v/v))

ESI-MS: (M+H)⁺=816/818/820 (Br₂) (M+2H)⁺⁺=408.6/409.6/410.6 (Br₂)

EXAMPLE 13

Preparation of compounds of general formula:

(R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(4-pyridinyl)-piperidine(No. 291)

A mixture of 0.97 g (1.8 mmol) of(R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoicacid, 0.48 g (1.8 mmol) of4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-piperidine, 2 ml oftriethylamine, 0.58 g (1.8 mmol) of TBTU, 0.24 g (1.8 mmol) of HOBt, 25ml of THF and 25 ml of DMF was stirred for 4 hours at ambienttemperature. The reaction mixture was evaporated down in vacuo, theresidue was taken up in a mixture of ethyl acetate and methanol (95/5(v/v)) and washed with saturated aqueous sodium hydrogen carbonatesolution. The organic phase was dried and evaporated down in vacuo. Theresidue was purified by column chromatography (MN-silica gel 60,Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=9/1(v/v); then MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:methylene chloride/ethanol=9/1 (v/v)). 0.2 g (15% of theory) of thedesired product were obtained as a white amorphous solid.

IR (KBr): 1668.3 cm⁻¹ (C═O)

R_(f): 0.5 (FM2)

ESI-MS: (M+H)⁺=737/739/741 (Br₂) (M+Na)⁺=759/761/763 (Br₂)

The following were prepared analogously:

% No. RCO R² NR³R⁴ Yield MS R_(f) Eluant IR [cm⁻¹] 291 N66 AS4 C4 15ESI: (M + H)⁺ = 0,36 CH₂Cl₂/ (KBr): C═O 737/39/41 (Br₂) EtOH 1668 296N66 AS4 C8 14 ESI: (M + H)⁺ = 0,66 FM1 (KBr): C═O 743/5/7 (Br₂) 1668 302N71 AS4 C8 19 ESI: (M + H)⁺ = 0,54 FM1 (KBr): C═O 755/7/9 (Br₂) 1682

EXAMPLE 14

1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine(No. 312)

a)1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine(No. 307)

Prepared analogously to Example 3 from methyl3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate,1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine andCDT in a yield of 27.2% of theory. Colourless, amorphous substance, Rf0.5 (eluant: dichloromethane/cyclohexane/methanol/conc.ammonia=7/1.5/1.5/0.2 (v/v/v/v)).

IR(KBr): 1718.5, 1670.3, 1618.2 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=796/798/800 (Br₂) (M+Na)⁺=818/820/822 (Br₂)

The following were obtained accordingly:

Frommethyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate,1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine andCDT in a yield of 30.3% of theory:1-4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine (No. 304), R_(f)=0.75(FM1).

IR(KBr): 1720.4, 1668.3, 1620.1 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=802/804/806 (Br₂) (M+Na)⁺=824/826/828 (Br₂)

Frommethyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate,1-(3,5-dibromo-D-tyrosyl)-4-(1-piperidinyl)-piperidine and CDT in ayield of 35% of theory:1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine(No. 422), R_(f) 0.54 (eluant:dichloromethane/cyclohexane/methanol/conc. ammonia=7/1.5/1.5/0.2(v/v/v/v)).

IR(KBr): 1720.4, 1668.3, 1627.8 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=803/805/807 (Br₂) (M+Na)⁺=825/827/829 (Br₂)

Frommethyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate,1-(3,5-dibromo-D-tyrosyl)-4-(4-pyridinyl)-piperidine and CDT in a yieldof 45% of theory:1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine(No. 420), R_(f) 0.56 (FM1).

IR(KBr): 1718.5, 1664.5, 1624.0 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=797/799/801 (Br₂) (M+Na)⁺=819/821/823 (Br₂)

b)1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine(No. 309)

Prepared analogously to Example A37) from1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)piperidineby saponification with lithium hydroxide in a yield of 95% of theory.Colourless, amorphous substance, R_(f) 0.25 (eluant:dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).

IR(KBr): 1666.4, 1614.3 cm⁻¹ (C═O)

ESI-MS: (M-H)⁻=780/782/784 (Br₂)

The following were obtained accordingly:

From1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidinein a yield of 60.2% of theory:1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-pIperidinyl]carbonyl]-D-phenlalanyl]-4-(1-piperidinyl)-piperidin(No. 306), R_(f) 0.15 (FM1).

IR(KBr): 1635.5 cm⁻¹, broad (C═O)

ESI-MS: (M+H)⁺=788/790/792 (Br₂) (M+Na)⁺=810/812/814 (Br₂)

From1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidinein a yield of 62% of theory:1-[3,5-dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine(No. 423), R_(f) 0.03 (eluant:dichloromethane/cyclohexane/methanol/conc. ammonia=7/1.5/1.5/0.2(v/v/v/v)).

IR(KBr): 1635.5 cm⁻¹, broad (C═O)

ESI-MS: (M+H)⁺=789/791/793 (Br₂)

From1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(methoxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidinein a yield of 80% of theory:1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine(No. 151). Colourless, amorphous substance.

IR(KBr): 1701.1, 1625.9 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=767/769/771 (Br₂) (M+2H)⁺⁺=383/384/385 (Br₂)

From1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidinein a yield of 82% of theory:1-[3,5-dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine(No. 421), R_(f) 0.03 (FM1). Colourless, amorphous substance.

IR(KBr): 1625 wide cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=783/785/787 (Br₂) (M+Na)⁺=805/807/809 (Br₂)

c)1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine(No. 312)

Prepared analogously to Example 1 from1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidineand ammonium carbonate in the presence of TBTU in a yield of 40.6% oftheory. Colourless, amorphous substance, R_(f) 0.8 (eluant:dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).

IR(KBr): 1670.3, 1616.3 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=781/783/785 (Br₂) (M+Na)⁺=803/805/807 (Br₂)

The following were obtained accordingly:

From1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidineand ethanolamine in a yield of 34.6% of theory:1-[4-amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenyalanyl]-4-(4-pyridinyl)-piperidine,(No. 313) R_(f)=0.7 (eluant: dichloromethane/methanol/conc.ammonia=7.5/2.5/0.5 v/v/v).

IR(KBr): 1662.5, 1618.2 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=825/827/829 (Br₂) (M+Na)⁺=847/849/851 (Br₂)(M+2H)⁺⁺=413/414/415 (Br₂) (M+H+Na)⁺⁺=424/425/426 (Br₂)

From1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidineand 1-methylpiperazine in a yield of 44.9% of theory:1-[4-amino-3,5-dibromo-N-[[-4-[7-[(4-methyl-1-piperazinyl)carbonyl]-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine,(No. 430) R_(f)=0.28 (eluant: ethyl acetate/methanol/conc.ammonia=8/1.5/0.3 v/v/v).

IR(KBr): 1618.2 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=864/866/868 (Br₂) (M+Na)⁺=886/888/890 (Br₂)(M+2H)⁺⁺=432/433/434.7 (Br₂)

From1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidineand methylammonium chloride in a yield of 37% of theory:1-[4-amino-3,5-dibromo-N-[[4-[7-(methylaminocarbonyl)-3,4-dihydro-2(1H)-onoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine,(No. 424) R_(f)=0.49 (FM1)

IR(KBr): 1662.5, 1622 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=795/797/799 (Br₂) (M+Na)⁺=817/819/821 (Br₂)

From1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2((1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl)]-4-(1-piperidinyl)-piperidineand ammonium carbonate in a yield of 12% of theory:1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1)-piperidinyl)-piperidine(No. 310), R_(f)=0.7 (eluant: dichloromethane/methanol/conc.ammonia=7.5/2.5/0.5 (v/v/v)).

IR(KBr): 1670.3, 1618.2 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=787/789/791 (Br₂)

From1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidineand ethanolamine in a yield of 11.4% of theory:1-[4-amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine(No. 311), R_(f)=0.65 (eluant: dichloromethane/methanol/conc.ammonia=7.5/2.5/0.5 (v/v/v)).

IR(KBr): 1660.6, 1620.1 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=831/833/835 (Br₂) (M+2H)⁺⁺=416/417/418 (Br₂)(M+H+Na)⁺⁺=427/428/429 (Br₂)

EXAMPLE 15

4-(1-acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-phenylalanyl]-piperidine(No. 372)

a)1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine

A mixture of 5.60 g (0.01 mol) of4-amino-3,5-dibromo-N²-(9-fluorenylmethoxycarbonyl)-D-phenylalanine,1.35 g (0.01 mol) HOBt, 3.21 g (0.01 mol) TBTU, 1.29 g (0.01 mol) DIEA,2.68 g (0.01 mol)4-[1-(1,1-dimethylethyl-oxycarbonyl)-4-piperidinyl]-piperidine and 150ml of tetrahydrofuran was stirred for 2 hours at room temperature. Afterthe reaction was complete 20 ml of diethylamine were added and themixture was stirred for a further 18 hours at room temperature. Thereaction mixture was evaporated down in vacuo, the residue was taken upin 200 ml of dichloromethane and washed successively with 100 ml ofsaturated sodium chloride solution and saturated sodium hydrogencarbonate solution and dried over magnesium sulphate. The reddish oilremaining after elimination of the solvent was purified by columnchromatography on silica gel (30-60 μm) using firstly dichloromethane,then FM4 as eluant. The title compound was obtained in the form of acolourless amorphous substance and in a yield of 4.31 g (73.3% oftheory).

IR(KBr): 1687.6 cm⁻¹ (C═O)

MS: M⁺=586/588/590 (Br₂)

b)1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine

Prepared analogously to Example 4 from1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine,CDT and 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in aquantitative yield. Colourless, amorphous substance.

IR(KBr): 1676 cm⁻¹ (C═O)

MS: (M+H)⁺=844/846/848 (Br₂) (M+Na)⁺=866/868/870 (Br₂)

c)1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine(No. 521)

Prepared analogously to Example A1b), but using sodium hydroxidesolution instead of ammonia, from1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidineby treating with trifluoroacetic acid in a yield of 75% of theory.Colourless, amorphous substance.

IR(KBr): 1666.4, 1620.1 cm⁻¹ (C═O)

MS: (M+H)⁺=744/746/748 (Br₂) (M+2H)⁺⁺=372/373/374.5 (Br₂)

d)4-(1-acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl-piperidine(No. 372)

A solution of 0.372 g (0.499 mmol) of1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidineand 0.07 g (5.5 mmol) of DIEA in 50 ml of dichloromethane was mixed with0.043 g (5.48 mmol) of acetylene chloride dropwise whilst coolingexternally with ice-water and then stirred for 1 hour at roomtemperature. The solvent was eliminated in vacuo, the residue wasstirred with water and filtered. The filter residue was dried in vacuoand purified by column chromatography on silica gel (30-60 μm) using FM4as eluant. The suitable eluates were evaporated down, the residue wastriturated with diethylether and suction filtered. 230 mg (58.5% oftheory) of colourless crystals were obtained.

IR(KBr): 1622 cm⁻¹ (C═O)

MS: (M+H)⁺=786/788/790 (Br₂) (M+Na)⁺=808/810/812 (Br₂)

The following were obtained accordingly:

1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-benzoyl-4-piperidinyl)-piperidine(No. (485).

Colourless crystals

R_(f) 0.74 (FM1)

IR(KBr): 1626, 1668 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=848/850/852 (Br₂)

EXAMPLE 16

1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine(No. 486)

A solution of 0.372 g (0.499 mmol) of1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidineand 0.07 g (5.5 mmol) of DIEA in 50 ml of dichloromethane was mixeddropwise with 0.063 g (5.5 mmol) of methanesulphonylchloride whilstcooling externally with ice-water and then stirred for 1 hour at roomtemperature. The solvent was eliminated in vacuo, the residue wasstirred with water and filtered. The filter residue was dried in vacuoand purified by column chromatography over silica gel (30-60 μm) usinginitially dichloromethane, then FM4 as eluant. The suitable eluates wereevaporated down, the residue was triturated with diethylether andsuction filtered. 220 mg (53.5% of theory) of colourless crystals wereobtained.

IR(KBr): 1668, 1618 cm⁻¹ (C═O)

MS: (M+H)⁺=822/824/826 (Br₂) (M+Na)⁺=844/846/848 (Br₂)(M+K)⁺=860/862/864 (Br₂)

The following were obtained accordingly:

(1)1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-(methylsulphonyloxy)-D-phenylalanyl]-4-[1-(methylsulphonyl)-4piperidinyl]-piperidine(No. (523)) in a yield of 12% of theory.

R_(f) 0.54 (FM1)

IR(KBr): 1628, 1665 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=901/903/905 (Br₂)

(2)1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine(No. (524) in a yield of 12% of theory.

R_(f) 0.50 (FM1)

ESI-MS: (M+H)⁺=823/825/827 (Br₂)

(3)(R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine(No. (668) in a yield of 56% of theory.

R_(f) 0.70 (FM1)

IR(KBr): 1630, 1666 cm⁻¹ (C═O)

MS: M⁺=699

EXAMPLE 17

1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(3-carboxy-1-oxopropyl)-4-piperidinyl]-piperidine(No. 487)

A mixture of 0.372 g (0.499 mmol) of1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine,0.11 g (1.1 mmol) of succinic anhydride and 150 ml of tetrahydrofuranwas refluxed for 1 hour. The reaction mixture was freed from solvent invacuo, the residue was purified by column chromatography on silica gel(30-60 μm) using FM1 as eluant. The suitable eluates were evaporateddown, the residue was triturated with diethylether and suction filtered.175 mg (41.5% of theory) of colourless crystals were obtained.

IR(KBr): 1668, 1608 cm⁻¹ (C═O)

MS: (M−H)⁻=842/844/846 (Br₂) (M+Na)⁺=868/870/872 (Br₂)

EXAMPLE 18

1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine(No. 488)

A mixture of 0.372 g (0.499 mmol) of1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine,0.05 g (0.499 mmol) of hexanal, 0.03 g (0.5 mmol) of glacial acetic acidand 150 ml of tetrahydrofuran was stirred for 1 hour at roomtemperature. After the addition of 0.116 g (0.52 mmol) of 95% sodiumtriacetoxyborohydride the mixture was kept for a further 2.5 hours atroom temperature. The solvent was eliminated in vacuo, the residue wasdivided between 20% aqueous sodium carbonate solution anddichloromethane, the organic phase was dried over magnesium sulphate andevaporated down. The residue was purified by column chromatography onsilica gel (30-60 μm) using FM4 as eluant. The suitable eluates wereevaporated down, the residue was triturated with diethylether andsuction filtered. 100 mg (24.2% of theory) of colourless crystals wereobtained.

IR(KBr): 1666, 1620 cm⁻¹ (C═O)

MS: (M+H)⁺=828/830/832 (Br₂) (M+Na)⁺=850/852/854 (Br₂)

The following were obtained accordingly:

(1)1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperdinyl]carbonyl]-D-pbenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidine(No. (489) in a yield of 23% of theory.

R_(f) 0.65 (FM1)

IR(KBr): 1622, 1666 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=798/800/802 (Br₂)

(2)1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine(No. (493) in a yield of 43% of theory.

R_(f) 0.72 (FM1)

IR(KBr): 1620, 1666 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=730/732/734 (Br₂)

(3)1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidine(No. (525) in a yield of 46.5% of theory.

R_(f) 0.50 (FM1)

IR(KBr): 1622, 1662 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=799/801/803 (Br₂)

EXAMPLE 19

Preparation of compounds of general formula:

1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine(No. 532)

The mixture of 200 mg (3 mmol)1-[3-bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine,108 mg (0.33 mMol) vinyl-tributyl tin (ALDRICH No. 27143-8), 50 mgtetrakis-(triphenylphosphine)-palladium (Merck No. 818193), a trace of2,6-di-tert.-butyl-4-methylphenol and 10 ml anhydrous toluene wasrefluxed for 5 hours. The cooled reaction mixture was filtered over anactivated charcoal filter, the filtrate was evaporated in a vacuum. Theresidue was purified for elution by column chromatography over silicagel, initially using pure dichloromethane, then methanol/conc. ammonia(9/1 v/v). The suitable eluates were triturated and suction filteredwith tert.-butyl-methylether. Yield was 60 mg (32.6% of theory) ofcolourless crystals of R_(f) 0.25 (FM1)

MS: M⁺=612

The following were prepared analogously: (in each case, n=1):

% No. RCO Z R² A NR³R⁴ Yield MS Eluant R_(f) IR [cm⁻¹] 647 N66 CH₂ AS40A0 C8 75 EI: M⁺ = 611 FM1 0.6 (KBr): C═O 1639/1668 648 N66 CH₂ AS41 A0C8 56 EI: M⁺ = 647 FM1 0.7 (KBr): C═O 1639/1668 649 N66 CH₂ AS42 A0 C8 8 EI: M⁺ = 648 FM1 0.6 (KBr): C═O 1635/1668 650 N66 CH₂ AS43 A0 C8 11EI: M⁺ = 654 FM1 0.6 (KBr): C═O 1635/1666 651 N66 CH₂ AS44 A0 C8 84 EI:M⁺ = 637 FM1 0.6 (KBr): C═O 1633/1664 652 N66 CH₂ AS45 A0 C8 83 EI: M⁺ =613 FM1 0.6 (KBr): C═O 1637/1667

EXAMPLE 20

Preparation of compounds of general formula:

(R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidin(No. 599)

Produced analogously to Example 1 from(R,S)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-4-oxobutanoicacid, 4-(4-methyl-1-piperazinyl)piperidine and TBTU in a yield of 10% oftheory. Colourless, amorphous substance of R_(f)=0.2(dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v).

IR(KBr): 1722, 1662, 1637 cm⁻¹ (C═O)

MS: M⁺=711

Accordingly,(R,S)-1-[4-[4-(aminocarbonylamino)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine(No. 601) was obtained from(R,S)-4-[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-4-oxobutanoicacid, 4-(4-methyl-1-piperazinyl)piperidine and TBTU in a yield of 20% oftheory. Colourless, amorphous substance of R_(f)=0.25(dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v).

ESI-MS: (M+H)⁺=624 (M+Na)⁺=646 (M+H+Na)⁺⁺=323.8

EXAMPLE 21

1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hydroxycarbonyl)-piperidine(No. 211)

Produced analogously to Example A38 from1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(ethoxycarbonyl)-piperidineand aqueous lithium hydroxide solution in a yield of 79% of theory.Colourless, amorphous substance of R_(f) 0.54 (ethylethanoate/methanol/glacial acetic acid 9/1/0.3 v/v/v).

IR(KBr): 1691.5, 1622.0 cm⁻¹ (C═O)

ESI-MS: (M-H)⁻=690/2/4 (Br₂)

EXAMPLE 22

1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperazine(No. 214)

Produced analogously to Example A24 from3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosine,1-(1,1-dimethylethoxycarbonyl)-4-(1-piperazinyl)piperidine and TBTU, andadditional conversion of the obtained intermediate product withtrifluoroacetic acid (in accordance with Example A1b) in a yield of 4.2%of theory. Colourless, amorphous substance of R_(f) 0.25 (FM1)

IR(KBr): 1624.0 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=732/4/6 (Br₂)

EXAMPLE 23

(R)-1-[2-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine(No.219)

a)1-(chlorocarbonyl)-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidine

To a solution of 3.0 g (13.8 mmol)4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)piperidine and 2.7 ml (15mMol) DIEA in 100 ml toluene, a solution of 1.8 ml (14.9 mMol)diphosgene in 15 ml toluene was added dropwise under external coolingwith iced water, and the mixture was additionally kept at roomtemperature for 17 hours. The precipitate was suction filtered, washedwith petroleum ether and dissolved in 50 ml dichloromethane. Theobtained solution was agitated twice each with 50 ml 7% aqueous sodiumhydrogen carbonate solution, dried over sodium sulphate and evaporatedin a vacuum. Yield was 3.0 g (78% of theory) of a colourless substanceof R_(f) 0.25 (dichloromethane/acetone 9/1 v/v), which was furtherprocessed without more purification.

b)(R)-1-[3-(3,5-dibromo-4-hydroxyphenyl)-2-(N-methylamino)-propyl]-4-(1-piperidin)-piperidine

To a suspension of 2.3 g (60 mmol) lithium aluminium hydride in 100 mlanhydrous tetrahydrofuran, a solution of 11.0 g (18.66 mmol)1-[3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-tyrosyl]-4-(1-piperidinyl)piperidinein 100 ml anhydrous tetrahydrofuran was added dropwise at roomtemperature whilst being stirred. It was stirred for a further 15minutes at room temperature and then refluxed for 3 hours. 3 ml 20%aqueous ammonium chloride solution was added to the cooled mixture, thenit was dried with magnesium sulphate. The filter cake was filtered andwashed with 300 ml of an ethyl ethanoate-methanol mixture (1/1 v/v), andthe combined filtrates were evaporated in a vacuum. The residue waspurified by column chromatography over silica gel using ethylethanoate/methanol (8/2 v/v) for elution.

1. 2.9 g (31% of theory) of a colourless substance of R_(f) 0.13(eluant: methanol) was isolated from the suitable fractions, which wasidentified as1-(3,5-dibromo-N-methyl-D-tyrosyl)-4-(1-piperidinyl)piperidine:

IR(KBr): 1668.3 cm⁻¹ (C═O)

MS: M⁺=501/3/5 (Br₂) and

2. 1.8 g (20% of theory) of a colourless substance of R_(f) 0.05(eluant: methanol), which was identified as the sought compound:

ESI-MS: (M+H)⁺=488/490/492 (Br₂) (M+2H)⁺⁺=244/245/246.5 (Br₂)

c)(R)-1-[2-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxy-phenyl)-propyl]-4-(1-piperidinyl)-piperidine(No. 219)

A solution of 0.57 g (2.02 mmol)1-(chlorocarbonyl)-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidinein 30 ml dimethylformamide was added dropwise to the mixture of 0.9 g(1.84 mmol)(R)-1-[3-(3,5-dibromo-4-hydroxyphenyl)-2-(N-methylamino)-propyl]-4-(1-piperidinyl)-piperidineand 0.65 ml (3.7 mmol) DIEA in a mixture of 50 ml tetrahydrofuran and 20ml dimethylformamide. It was stirred overnight at room temperature andthe deposit was evaporated in a vacuum. The residue was treated with 300ml of a tetrahydrofuran ethyl ethanoate mixture (1/1 v/v) and theresulting solution was agitated twice each with 100 ml of a saturatedaqueous solution of sodium hydrogen carbonate, dried over sodiumsulphate and evaporated in a vacuum. The residue was purified oversilica gel by column chromatography using dichloromethane/methanol(8.5/1.5 v/v) for elution. 390 mg (29% of theory) of a colourlesssubstance of R_(f) 0.46 (dichloromethane cyclohexane/methanol/conc.ammonia 75/15/15/2 v/v/v/v) were isolated from the suitable fractions:

IR(KBr): 1695.3, 1624.0 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=731/3/5 (Br₂)

EXAMPLE 24

1-[3,5-dibromo-N-[[4-[5-[(4-morpholinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine(No. 223)

100 mg (0.6 mMol) N,N′-carbonyldiimidazole was added to a solution of400 mg (0.5 mMol)1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidinein 10 ml anhydrous tetrahydrofuran at room temperature, heated to 50° C.for 30 minutes and then 90 mg (1 mMol) morpholine was added. Afterheating to 50-60° C. for two hours, the solution was removed in a vacuumand the residue was purified over silica gel(30-60 μm) by columnchromatography, initially using dichloromethane, thendichloromethane/methanol 9/1 (v/v), and finallydichloromethane/methanol/conc. ammonia 9/1/0.2 (v/v/v) as eluants. 250mg (60% of theory) of an amorphous, colourless substance was yieldedfrom the suitable extracts.

IR(KBr): 1712.7, 1625.9 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=838/840/842 (Br₂) (M+2H)⁺⁺=419/420/421.5 (Br₂)

The following were obtained accordingly:

1-[3,5-dibromo-N-[[4-[5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine(No. 224) from1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimi-dazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine,1-methylpiperazine and N,N′-carbonyldiimidazole in a yield of 52% oftheory. Colourless, amorphous substance.

IR(KBr): 1710.8, 1625.9 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=851/853/855 (Br₂) (M+2H)⁺⁺=426/427/428 (Br₂)

EXAMPLE 25

1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(carboxymethyl)-4-piperidinyl]-piperidine(No. 494)

Produced analogously to Example A37, but using tetrahydrofuran insteadof methanol, from1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidineby the action of aqueous lithium hydroxide solution in a yield of 51% oftheory. Colourless, amorphous substance.

ESI-MS: (M−H)⁻=800/802/804 (Br₂) (M+H)⁺=802/804/806 (Br₂)(M+Na)⁺=824/826/828 (Br₂)

EXAMPLE 26

1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine(No. 526)

Produced analogously to Example 18 from1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine,ethyl glyoxylate and sodium triacetoxyborhydride and additionalsaponification with soda lye of the1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine,obtained as an intermediate product but not characterised, according toExample A55. A colourless, amorphous substance is obtained in a yield of35% of theory.

IR(KBr): 1625.9 wide cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=803/805/807 (Br₂) (M+Na)⁺=825/827/829 (Br₂)

EXAMPLE 27

1-[4-amino-N-[(4-amino-1-piperidinyl)carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine(No. 564)

653 mg (10.4 mMol) 95% sodium cyanoborohydride (Aldrich 15.615-9) wasstirred into the mixture of 930 mg (1.48 mMol)1-[4-amino-3,5-dibromo-N-[(4-oxo-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine,1143 mg (14.8 mMol) ammonium acetate (Merck No. 1115) and 30 mlanhydrous methanol at room temperature, and was stirred overnight. Thedeposit was adjusted to pH≦2 with conc. hydrochloric acid and wasevaporated in a vacuum. The residue is taken up in water and madealkaline with 40% soda lye. Exhaustive extraction with dichloromethanefollowed, then the combined extracts were dried over sodium sulphate andevaporated in a vacuum. The residue was purified over 100 g silica gel(Amicon, 35-70 μm) by column chromatography usingdichloromethane/methanol/conc. ammonia(60/40/5 v/v/v) for elution. Fromthe suitable fractions, 250 mg (270% of theory) of the sought substancewas isolated as a colourless, amorphous product of R_(f) 0.15(dichloromethane/methanol/conc. ammonia 50/50/0.5 v/v/v).

IR(KBr): 1618 wide cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=627/629/631 (Br₂) (M+Na)⁺=649/651/653 (Br₂)(M+2H)⁺⁺=314/315/316 (Br₂)

EXAMPLE 28

(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorphenyl)methyl]-1,4-dioxobutyl]-4-(hydroxycarbonylmethyl)-piperidine(No. 596)

Produced analogously to Example A55 from(R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonylmethyl)-piperidineby saponification with soda lye in a yield of 866 of theory. Colourless,amorphous substance of R_(f) 0.76 (ethyl ethanoate/methanol/glacialacetic acid 70/30/1 v/v/v).

IR(KBr): 1716, 1635 cm⁻¹ (C═O)

ESI-MS: (M−H)⁻=613/615/617 (Cl₂) (M+H)⁺=615/617/619 (Cl₂)(M+Na)⁺=637/639/641 (C12)

EXAMPLE 29

1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-carbonyl]-3-(1H-tetrazol-5-yl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine(No. 632)

8.5 g (35 mMol) tributyl tin(IV)-azide (Synthesis 1976, 330) was addedto a solution of 1.6 g (2.68 mMol)1-[3-cyano-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidinein 400 ml toluene and the mixture was refluxed for 4 days. The residueremaining after dispellation of the solvent was stirred with ethylethanoate, the obtained precipitate was suction filtered and purifiedover silica gel by column chromatography using FM1 as an eluent. Afterthe usual further processing, yield is 400 mg (24% of theory) ofcolourless crystals of R_(f) 0.2 (FM1)

IR(KBr): 1653 cm⁻¹ (C═O)

ESI-MS: (M+H)⁺=641 (M+Na)⁺=663

The following Examples describe the preparation of pharmaceuticallyuseful forms which contain as active substance any desired compound ofgeneral formula I:

EXAMPLE I

Calpsules for Powder Inhalation Containing 1 mg of Active Substance

Composition:

1 capsule for powder inhalation contains:

Active substance 1.0 mg Lactose 20.0 mg Hard gelatine capsules 50.0 mg71.0 mg

Method of Preparation

The active substance is ground to the particle size required forinhalants. The ground active substance is homogeneously mixed with thelactose. The mixture is packed into hard gelatine capsules.

EXAMPLE II

Inhalable Solution for Respimat® Containing 1 mg of Active Substance

Composition:

1 stroke contains:

Active substance 1.0 mg Benzalkonium chloride 0.002 mg Disodium edetate0.0075 mg Purified water ad 15.0 μl

Method of Preparation

The active substance and benzalkonium chloride are dissolved in waterand transferred into Respimat® cartridges.

EXAMPLE III

Inhalable Solution for Nebulisers Containing 1 mg of Active Substance

Composition:

1 vial contains:

Active substance 0.1 g Sodium chloride 0.18 g Benzalkonium chloride0.002 g Purified water ad 20.0 ml

Method of Preparation

Active substance, sodium chloride and benzalkonium chloride aredissolved in water.

EXAMPLE IV

Propellant Gas Metering Aerosol Containing 1 mg of Active Substance

Composition:

1 stroke contains:

Active substance 1.0 mg Lecithin 0.1 % Propellant gas ad 50.0 μl

Method of Preparation

The micronised active substance is homogeneously suspended in a mixtureof lecithin and propellant gas. The suspension is transferred into apressurised container with metering valve.

EXAMPLE V

Nasal Spray Containing 1 mg of Active Substance

Composition:

Active substance 1.0 mg Sodium chloride 0.9 mg Benzalkonium chloride0.025 mg Disodium edetate 0.05 mg Purified water ad 0.1 ml

Method of Preparation

The active substance and adjuvants are dissolved in water andtransferred into a suitable container.

EXAMPLE VI

Injectable Solution Containing 5 mg of Active Substance Per 5 mg

Composition:

Active substance 5 mg Glucose 250 mg Human-serum-albumin 10 mgGlycofurol 250 mg Water for injections ad 5 ml

Preparation

Glycofurol and glucose are dissolved in water for injections (WfI);human-serum-album in is added; active substance is dissolved withheating; solution is made up to required volume with WfI; transferredinto ampoules under nitrogen gas.

EXAMPLE VII

Injectable Solution Containing 100 mg of Active Substance Per 20 mg

Composition:

Active substance 100 mg Monopotassium dihydrogen phosphate = KH₂PO₄ 12mg Disodium hydrogen phosphate = Na₂HPO₄.2H₂O 2 mg Sodium chloride 180mg Human-serum-albumin 50 mg Polysorbate 80 20 mg Water for injectionsad 20 ml

Preparation

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate anddisodium hydrogen phosphate are dissolved in water for injections (WfI);human-serum-albumin is added; active substance is dissolved withheating; solution is made up to required volume with WfI; transferredinto ampoules.

EXAMPLE VIII

Lysophilisate Containing 10 mg of Active Substance

Composition:

Active substance 10 mg Mannitol 300 mg Human-serum-albumin 20 mg

Preparation

Mannitol is dissolved in water for injections (WfI); human-serum-albuminis added; active substance is dissolved with heating; solution is madeup to required volume with WfI; transferred into vials and freeze-dried.

Solvent for lyophilisate:

Polysorbate 80 = Tween 80 20 mg Mannitol 200 mg Water for injections ad10 ml

Preparation

Polysorbate 80 and mannitol are dissolved in water for injections (WfI)and transferred into ampoules.

EXAMPLE IX

Tablets Containing 20 mg of Active Substance

Composition:

Active substance 20 mg Lactose 120 mg Corn starch 40 mg Magnesiumstearate 2 mg Povidon K 25 18 mg

Preparation

Active substance, lactose and corn starch are homogeneously mixed;granulated with an aqueous solution of Povidon; mixed with magnesiumstearate; pressed in a tablet press; weight of tablet 200 mg.

EXAMPLE X

Capsules Containing 20 mg of Active Substance

Composition:

Active substance 20 mg Corn starch 80 mg Highly dispersed silicic acid 5mg Magnesium stearate 2.5 mg

Preparation

Active substance, corn starch and silicic acid are homogeneously mixed;mixed with magnesium stearate; then the mixture is packed into size 3hard gelatine capsules using a capsule filling machine.

EXAMPLE XI

Suppositories Containing 50 mg of Active Substance

Composition:

Active substance 50 mg Hard fat (adeps solidus) q.s. ad 1700 mg

Preparation

Hard fat is melted at about 38° C.; ground active substance ishomogeneously dispersed in the molten hard fat; then after cooling toabout 35° C. the melt is poured into chilled moulds.

EXAMPLE XII

Aqueous Solution for Nasal Application Containing 10 mg Active Substance

Composition:

Active substance 10.0 mg Hydrochloric acid in quantity required forformation of a neutral salt Methylparahydroxybenzoate (PHB) 0.01 mgPropylparahydroxybenzoate (PHB) 0.005 mg Purified water ad 1.0 ml

Preparation

The active substance is dissolved in purified water; Hydrochloric acidis added until the solution is clear; PHB methyl and propyl esters areadded; the solution is made up to required volume with purified water;the solution is sterile-filtered and is transferred into an appropriatecontainer.

EXAMPLE XIII

Aqueous Solution for Nasal Application Containing 5 mg Active Substance

Composition:

Active substance 5 mg 1,2-propandiol 300 mg Hydroxyethylcellulose 5 mgSorbic acid 1 mg Purified water ad 1 ml

Preparation

The active substance is dissolved in 1,2-propandiol; ahydroxy-ethyl-cellulose solution is prepared in purified watercontaining sorbic acid and is added to the active substance solution;the solution is sterile-filtered and is transferred into an appropriatecontainer.

EXAMPLE XIV

Aqueous Solution for Intravenous Application Containing 5 mg ActiveSubstance

Composition:

Active substance 5 mg 1,2-propandiol 300 mg Mannitol 50 mg Water forinjections (WfI) ad 1 ml

Preparation

The active substance is dissolved in 1,2-propandiol; the solution isapproximately made up to the required volume with WfI; the mannitol isadded and the solution is made up to required volume with WfI; thesolution is sterile-filtered, transferred into individual containers andautoclaved.

EXAMPLE XV

Liposomal Formulation for Intravenous Injection Containing 7.5 mg ActiveSubstance

Composition:

Active substance 7.5 mg Egg-lecithin, e.g. lipoid E 80 100.0 mgCholesterol 50.0 mg Glycerine 50.0 mg Water for injections ad 1.0 ml

Preparation

The active substance is dissolved in a mixture of lecithin andcholesterol; the solution is added to a mixture of glycerine and WfI andis homogenised by means of high-pressure homogenisation ormicrofluidiser technology; the liposomal formulation obtained in thismanner is transferred into an appropriate container under asepticconditions.

EXAMPLE XVI

Suspension for Nasal Application Containing 20 mg Active Substance

Composition:

Active substance 20.0 mg Carboxymethylcellulose (CMC) 20.0 mg Sodiummonohydrogen phosphate/sodium- q.s. dihydrogen phosphate buffer pH 6.8Sodium chloride 8.0 mg Methylparahydroxybenzoate 0.01 mgPropylparahydroxybenzoate 0.003 mg Purified water ad 1.0 ml

Preparation

The active substance is suspended in an aqueous CMC solution; the othercomponents are added to the suspension one after another and thesuspension is made up to required volume with purified water.

EXAMPLE XVII

Aqueous Solution for Subcutaneous Application Containing 10 mg ActiveSubstance

Composition:

Active substance 10.0 mg Sodium monohydrogen phosphate/sodium 7.0dihydrogen phosphate buffer q.s. ad pH Sodium chloride 4.0 mg Water forinjections ad 0.5 ml

Preparation

The active substance is dissolved in the phosphate buffer solution,after addition of the sodium chloride the solution is made up torequired volume with water. The solution is sterile-filtered and isautoclaved after being transferred into an appropriate container.

EXAMPLE XVIII

Aqueous Solution for Subcutaneas Application Containing 5 mg ActiveSubstance

Composition:

Active substance 5.0 mg Polysorbate 80 0.5 mg Water for injections ad0.5 ml

Preparation

The active substance is suspended in the polysorbate 80 solution and isreduced to a particle size of approx. 1 μm by means of a suitabledispersion technique (e.g. wet milling, high-pressure homogenisation,micro-fluidisation, etc.). The suspension is transferred into anappropriate container under aseptic conditions.

What is claimed is: 1.1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazineor a physiologically acceptable salt or a tautomer thereof. 2.1-[4-Amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidineor a physiologically acceptable salt or a tautomer thereof.
 3. A methodfor the treatment of headaches, or morphine tolerance, which methodcomprises the administration of a compound in accordance with claim 1 or2.